Affinage

HIC1

Hypermethylated in cancer 1 protein · UniProt Q14526

Length
733 aa
Mass
76.5 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HIC1 is a sequence-specific transcriptional repressor that functions as a p53-inducible tumor suppressor and an enforcer of progenitor cell quiescence in adult tissues (PMID:7585125, PMID:31809738). It binds a GC-rich consensus sequence (GGCA core) through its C-terminal C2H2 zinc fingers, with the N-terminal BTB/POZ domain dimerizing and mediating cooperative binding to concatemerized sites (PMID:15231840). The BTB/POZ domain is an autonomous repression module that, unlike related BTB proteins, does not recruit SMRT/N-CoR or mSin3A/HDAC1 (PMID:10611298); instead HIC1 represses transcription by recruiting a panel of corepressor machineries—CtBP via a GLDLSKK motif in a redox/NADH-dependent manner (PMID:12052894, PMID:16762039), the NuRD subunit MTA1 (PMID:20547755), ARID1A/BRG1-containing SWI/SNF complexes (PMID:19486893, PMID:19015639), and PRC2 through the Polycomb-like proteins hPCL3/PHF1 (PMID:22315224). A central node of HIC1 function is direct repression of the SIRT1 deacetylase: HIC1/SIRT1 complexes bind the SIRT1 promoter, and loss of HIC1 raises SIRT1, which deacetylates and inactivates p53 to permit survival after DNA damage, forming a self-reinforcing tumor-suppressor loop (PMID:16269335). HIC1 repressive activity is governed by a competitive K314 acetylation/SUMOylation switch—SIRT1 and HDAC4 deacetylate K314 to favor SUMOylation, which enhances repression and MTA1 recruitment (PMID:17283066, PMID:23417673). HIC1 represses an extensive direct target program including ATOH1, E2F-responsive genes, p21, CXCR7, EphA2, ephrin-A1, ADRB2, TLR2, and IL-6, linking it to control of proliferation, differentiation, migration, and inflammatory signaling (PMID:18347096, PMID:19525223, PMID:20154726, PMID:22184117, PMID:22194601, PMID:19015639, PMID:25934696, PMID:23178572, PMID:27107418), and it antagonizes Wnt/TCF and STAT3 signaling by sequestering or displacing these factors from target promoters (PMID:16724116, PMID:24067369). In vivo, conditional deletion shows HIC1 maintains quiescence of skeletal-muscle mesenchymal progenitors and cardiac fibro/adipogenic progenitors (PMID:31809738, PMID:31978365) and regulates intestinal T-cell homeostasis downstream of retinoic acid (PMID:28327618).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 High

    Established HIC1 as a p53-regulated tumor suppressor, answering whether the hypermethylated locus encoded a functional growth-suppressive gene.

    Evidence p53 expression vector transfection with RT-PCR, identification of a 5' p53 binding site, and colony suppression in brain/breast/colon cancer cells

    PMID:7585125

    Open questions at the time
    • Did not define HIC1's DNA-binding specificity or repression mechanism
    • No direct target genes identified
  2. 1999 High

    Defined the BTB/POZ domain as an autonomous repression module that operates through a non-canonical, HDAC-independent route distinct from BCL-6/PLZF.

    Evidence Mammalian two-hybrid, in vivo/in vitro Co-IP for SMRT/N-CoR/mSin3A/HDAC1, and trichostatin A reporter assays

    PMID:10611298

    Open questions at the time
    • The actual corepressors recruited by the BTB/POZ domain were not identified
    • DNA-binding consensus still unknown
  3. 2002 High

    Identified CtBP as a HIC1 corepressor via the GLDLSKK motif, reconciling the earlier HDAC-independent observation by revealing both HDAC-independent (BTB/POZ) and HDAC-dependent (CtBP) repression arms.

    Evidence In vivo/in vitro Co-IP, mammalian two-hybrid, Gal4 reporter assays, trichostatin A sensitivity

    PMID:12052894

    Open questions at the time
    • Did not define which target promoters use the CtBP arm
    • Physiological regulation of the interaction not addressed
  4. 2004 High

    Defined the HIC1 DNA-binding consensus and the role of BTB/POZ in cooperative multisite binding, providing the basis for identifying direct targets.

    Evidence SELEX, EMSA, ChIP, luciferase reporters, deletion/mutagenesis; plus separate identification of O-GlcNAc sites in the DNA-binding domain

    PMID:15231840 PMID:15373830

    Open questions at the time
    • Genome-wide occupancy not mapped
    • Functional consequence of O-GlcNAc on full-length HIC1 unclear
  5. 2005 High

    Placed HIC1 at the apex of a SIRT1-p53 tumor-suppressor loop, explaining how HIC1 inactivation enables apoptosis bypass after DNA damage.

    Evidence Reciprocal Co-IP, ChIP of the SIRT1 promoter, reporter assays, and siRNA knockdown with apoptosis readout

    PMID:16269335

    Open questions at the time
    • Did not address how the HIC1/SIRT1 interaction is regulated
    • Other SIRT1-promoter corepressors not yet resolved
  6. 2006 Medium

    Extended HIC1 repression to Wnt signaling antagonism, showing it sequesters TCF-4/beta-catenin into nuclear bodies rather than only repressing classic targets.

    Evidence Co-IP, confocal imaging of nuclear bodies, Wnt-responsive luciferase reporters; plus mutagenesis showing CtBP binding is NADH-stimulated

    PMID:16724116 PMID:16762039

    Open questions at the time
    • Nuclear-body sequestration mechanism not structurally defined
    • In vivo relevance to Wnt-driven tumors not tested here
  7. 2007 High

    Revealed a K314 acetylation/SUMOylation switch and a metabolic/redox input via CtBP, explaining how HIC1 repression is dynamically tuned to nutrient and modification state.

    Evidence In vivo SUMOylation and in vitro P300/CBP acetylation assays, K314R/E316A mutagenesis, SIRT1 siRNA; plus 2-deoxyglucose modulation of CtBP association

    PMID:17213307 PMID:17283066

    Open questions at the time
    • SUMO E3 ligase and upstream signaling to K314 not fully defined
    • Direct downstream effect on target panels not enumerated
  8. 2008 High

    Linked HIC1 repression to developmental and oncogenic control by identifying ATOH1 as a direct target and demonstrating BRG1/SWI/SNF as a repression effector.

    Evidence ChIP, reporter assays, Ptch1/Hic1 compound-heterozygote medulloblastoma genetics; BRG1-dependent repression of E2F genes via ChIP/Co-IP in BRG1-null cells

    PMID:18347096 PMID:19015639

    Open questions at the time
    • How HIC1 selects SWI/SNF versus other corepressors at a given promoter unclear
    • ATOH1 repression mechanism (PRC2 involvement) not yet established
  9. 2009 Medium

    Broadened the direct HIC1 target repertoire (CXCR7) and established ARID1A-containing SWI/SNF recruitment as a defined corepressor pathway.

    Evidence Expression profiling, ChIP/sequential ChIP with CtBP, siRNA; yeast two-hybrid and reciprocal Co-IP in BRG1-/- cells for ARID1A

    PMID:19486893 PMID:19525223

    Open questions at the time
    • Determinants directing CtBP vs SWI/SNF complex choice unresolved
    • Reciprocal validation limited to single lab
  10. 2011 Medium

    Connected HIC1 loss to a pro-migratory/invasive program through direct repression of receptor genes EphA2 and ADRB2 via MTA1/NuRD recruitment.

    Evidence ChIP, sequential ChIP with MTA1, siRNA knockdown with migration and invasion assays

    PMID:22184117 PMID:22194601

    Open questions at the time
    • In vivo metastasis dependence on these specific targets not isolated
    • Single-lab functional assays
  11. 2012 Medium

    Defined PRC2 (via hPCL3/PHF1) as a HIC1 corepressor and mapped the SIRT1-dependent, phosphorylation-gated HIC1/SIRT1 interaction interface, integrating chromatin silencing with the deacetylation switch.

    Evidence Yeast two-hybrid, Co-IP, ChIP for EZH2 at ATOH1; SIRT1 domain mapping (ESA region) and CKII phosphorylation of SIRT1 S659/661; plus STAT3 sequestration identified by MS/Co-IP

    PMID:22315224 PMID:22510409 PMID:24067369

    Open questions at the time
    • How HIC1 coordinates PRC2 with NuRD/SWI/SNF at the same loci unclear
    • STAT3 antagonism mechanism not structurally resolved
  12. 2013 Medium

    Tied the SUMOylation switch to the DNA-damage response, showing DSBs drive HDAC4/Ubc9-dependent K314 SUMOylation that favors HIC1/MTA1 and promotes repair.

    Evidence Co-IP, in vivo SUMOylation, gammaH2AX foci, etoposide damage model, non-SUMOylatable mutants; plus direct repression of p21 by ChIP/siRNA

    PMID:23178572 PMID:23417673

    Open questions at the time
    • Direct enzymatic SUMO ligase identity incomplete
    • Single-lab functional readouts
  13. 2015 Medium

    Implicated HIC1 in restraining innate inflammatory signaling, showing direct TLR2 repression that limits NF-kB activity and colonic tumorigenesis.

    Evidence ChIP, conditional Cre/loxP knockout, intestinal organoids, chemical carcinogenesis model

    PMID:25934696

    Open questions at the time
    • Whether TLR2 derepression alone drives the tumor phenotype not isolated
    • Corepressor used at TLR2 not specified
  14. 2016 Medium

    Connected HIC1 loss to autocrine cytokine signaling (IL-6/STAT3) and to a viral transcription context, expanding its inflammatory and gene-regulatory reach.

    Evidence IL-6: ChIP, reporter, siRNA, rescue in NSCLC; HIV: Co-IP with CTIP2/HMGA1, K314 acetylation-dependent Tat repression

    PMID:27107418 PMID:27725726

    Open questions at the time
    • Direct vs indirect contributions of additional targets not separated
    • HIV repression generality untested
  15. 2017 Medium

    Dissociated HIC1's repair and apoptotic functions, showing SUMOylation is dispensable for DSB repair but required for the apoptotic transcriptional response to irreparable damage via ATM-dependent MTA1/MTA3 recruitment to SIRT1.

    Evidence Comet assay, gammaH2AX foci, Co-IP, ChIP, E316A mutant, ATM/Chk2 inhibitors, expression profiling

    PMID:27935866

    Open questions at the time
    • The damage-sensing step that distinguishes reparable vs irreparable DSBs is undefined
    • Single-lab study
  16. 2018 Medium

    Established tissue-level roles for HIC1 in immune homeostasis and the tumor microenvironment beyond cell-autonomous repression.

    Evidence T-cell-specific knockout with vitamin A-deficient diet and infection models; mammary-specific knockout linking HIC1 loss to CXCL14/GPR85 fibroblast activation; plus renal EZH2/DNMT1 recruitment to SIRT1 under high glucose

    PMID:28327618 PMID:30204129 PMID:30496037

    Open questions at the time
    • Direct HIC1 targets governing T-cell IL-17A output not fully mapped
    • Paracrine CXCL14 regulation may be indirect
  17. 2019 High

    Defined HIC1 as a marker and enforcer of adult mesenchymal/progenitor quiescence, establishing a homeostatic role distinct from its tumor-suppressor activity.

    Evidence Conditional knockout, scRNA-seq, ATAC-seq, lineage tracing in skeletal muscle; conditional knockout in cardiac PDGFRa+/SCA-1+ progenitors driving arrhythmogenic cardiomyopathy

    PMID:31809738 PMID:31978365

    Open questions at the time
    • Direct target genes maintaining quiescence not pinned down
    • Link between quiescence program and the SIRT1/p53 axis unexplored
  18. 2021 Medium

    Confirmed conserved ATOH1 repression in cochlear differentiation and added a degradation route (FBXW11) controlling HIC1 protein stability and downstream SIRT1.

    Evidence Cochlear organoid knockdown/overexpression with Atoh1 enhancer reporter and C521S DNA-binding mutant; FBXW11 Co-IP, ubiquitination assay, xenograft in colorectal cancer

    PMID:33770497 PMID:34642302

    Open questions at the time
    • Upstream signals controlling FBXW11-mediated turnover unclear
    • Whether degradation is regulated coordinately with the K314 switch unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HIC1 selects among its many corepressor complexes (CtBP, NuRD, SWI/SNF, PRC2) at individual promoters, and how the K314 switch, O-GlcNAcylation, and FBXW11-mediated turnover are integrated in vivo, remain unresolved.
  • No structural model of HIC1 corepressor selection
  • No genome-wide occupancy map integrating modification state
  • Mechanism coupling tumor-suppressor and quiescence programs undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2
Partners
ARID1ABRG1CTBPEZH2HDAC4MTA1SIRT1STAT3
Complex memberships
NuRDPRC2SWI/SNF (BRG1/ARID1A)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 HIC1 forms a transcriptional repression complex with SIRT1 deacetylase that directly binds the SIRT1 promoter and represses its transcription; inactivation of HIC1 results in upregulated SIRT1 expression, leading to deacetylation and inactivation of p53, allowing cells to bypass apoptosis after DNA damage. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), promoter reporter assays, siRNA knockdown with apoptosis readout Cell High 16269335
1995 HIC1 is activated transcriptionally by wild-type p53 (p53 binding site identified in the 5' flanking region) and suppresses colony formation in brain, breast, and colon cancer cells when inserted exogenously, establishing it as a p53-regulated tumor suppressor. p53 expression vector transfection with RT-PCR for HIC1 expression, colony suppression assay, sequence analysis of p53 binding site Nature medicine High 7585125
2007 HIC1 represses SIRT1 transcription through a metabolically regulated complex with the redox sensor CtBP; treatment with the glycolytic blocker 2-deoxyglucose decreases CtBP association with HIC1, thereby de-repressing SIRT1 expression in response to nutrient deprivation. Co-immunoprecipitation, promoter reporter assays, pharmacological treatment (2-deoxyglucose) Proceedings of the National Academy of Sciences of the United States of America Medium 17213307
2007 HIC1 is SUMOylated in vivo on lysine K314; this SUMOylation positively controls HIC1 transcriptional repression activity. HIC1 is also acetylated in vitro by P300/CBP on K314, creating a competitive acetylation/SUMOylation switch. SIRT1 and HDAC4 deacetylate K314 to favor SUMOylation; SIRT1 knockdown reduces HIC1 SUMOylation. In vivo SUMOylation assay, in vitro acetylation assay with P300/CBP, site-directed mutagenesis (K314R, E316A, P317A), siRNA knockdown of SIRT1, transfection reporter assays Molecular and cellular biology High 17283066
2002 HIC1 interacts with CtBP corepressor through a conserved GLDLSKK motif (a variant of the PxDLSxK/R CtBP interaction motif); BTB/POZ domain dimerization is required for this interaction. HIC1 mediates transcriptional repression via both HDAC-independent (BTB/POZ) and HDAC-dependent (CtBP-dependent) mechanisms. In vivo and in vitro Co-immunoprecipitation, mammalian two-hybrid, Gal4 fusion reporter assays, trichostatin A sensitivity assays Molecular and cellular biology High 12052894
1999 The BTB/POZ domain of HIC1 acts as an autonomous transcriptional repression domain but, unlike BCL-6 and PLZF, does not recruit SMRT/N-CoR, mSin3A, or HDAC-1 complexes in vivo or in vitro, and HIC1-mediated repression is not alleviated by the HDAC inhibitor trichostatin A. Mammalian two-hybrid, in vivo and in vitro Co-immunoprecipitation, trichostatin A treatment with reporter assay Proceedings of the National Academy of Sciences of the United States of America High 10611298
2004 HIC1 binds the consensus DNA sequence 5'-(C/G)NG(C/G)GGGCA(C/A)CC-3' (GGCA core motif bound by zinc fingers 3 and 4); the BTB/POZ domain inhibits binding to a single site but mediates cooperative binding to multiple concatemerized sites. Endogenous HIC1 represses transcription through direct binding to these sites, confirmed by ChIP. SELEX (selection and amplification of binding sites), electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), luciferase reporter assays, deletion/mutagenesis analysis The Journal of biological chemistry High 15231840
2006 HIC1 antagonizes TCF/beta-catenin-mediated transcription in Wnt-stimulated cells by associating with TCF-4 and recruiting TCF-4 and beta-catenin to HIC1 nuclear bodies, preventing their association with TCF-binding elements on Wnt-responsive gene promoters. Co-immunoprecipitation, immunofluorescence/confocal microscopy (nuclear body co-localization), luciferase reporter assays for Wnt-responsive transcription The EMBO journal Medium 16724116
2008 HIC1 is a direct transcriptional repressor of ATOH1 (Atonal Homolog 1); loss of HIC1 in mouse GCPs leads to increased ATOH1 expression, and compound Ptch1/Hic1 heterozygotes show fourfold increased medulloblastoma incidence compared with Ptch1 heterozygotes alone. Chromatin immunoprecipitation (ChIP), luciferase reporter assays, mouse genetic epistasis (compound heterozygotes), in vitro growth assays with ATOH1 knockdown Genes & development High 18347096
2009 CXCR7 is a direct transcriptional target gene of HIC1; endogenous HIC1 binds the CXCR7 promoter together with CtBP corepressor; siRNA knockdown of HIC1 in WI38 fibroblasts upregulates CXCR7. Genome-wide expression profiling, quantitative RT-PCR, luciferase reporter/promoter deletion assays, ChIP and sequential ChIP (ChIP-on-ChIP), siRNA knockdown The Journal of biological chemistry High 19525223
2009 HIC1 interacts with and represses ARID1A/BAF250A-containing SWI/SNF complexes; Co-IP in WI38 fibroblasts and BRG1-/- SW13 cells showed that endogenous HIC1 and ARID1A interact in a BRG1-dependent manner; sequential ChIP demonstrated HIC1 represses E2F1 via recruitment of ARID1A-containing SWI/SNF complexes. HIC1 does not interact with BRM. Yeast two-hybrid, co-immunoprecipitation (reciprocal, in BRG1-/- cells), sequential ChIP (ChIP-reChIP) Biochemical and biophysical research communications Medium 19486893
2010 HIC1 interacts with MTA1 (a subunit of the NuRD complex) as a new corepressor; this interaction is regulated by competitive posttranslational modifications at K314 (SUMOylation promotes, acetylation inhibits). HIC1/MTA1 complexes bind Cyclin D1 and p57KIP2 promoters in quiescent cells; HIC1/MTA1 and HIC1/CtBP complexes differentially occupy distinct HIC1-responsive elements on the SIRT1 promoter. Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), sequential ChIP Molecular and cellular biology High 20547755
2010 HIC1 is a direct transcriptional repressor of ephrin-A1; mouse embryos lacking both Hic1 alleles show developmental defects spatially associated with ephrin-A1 misexpression; re-expression of HIC1 in breast cancer cells reduces tumor growth, partially rescued by ephrin-A1 co-overexpression. ChIP, luciferase reporter assays, mouse knockout/heterozygote in vivo model, in vivo tumor growth rescue experiment Oncogene Medium 20154726
2011 EphA2 is a direct transcriptional target gene of HIC1; endogenous HIC1 proteins are bound together with MTA1 corepressor to the EphA2 promoter in WI38 cells; siRNA knockdown of HIC1 in normal breast epithelial cells upregulates EphA2 and increases cellular migration. Chromatin immunoprecipitation (ChIP), sequential ChIP, RT-PCR and Western blot, siRNA knockdown with migration assay The Journal of biological chemistry Medium 22184117
2011 HIC1 is a direct transcriptional repressor of the β-2 adrenergic receptor (ADRB2); agonist-mediated stimulation of ADRB2 increases migration and invasion of breast cancer cells, effects abolished by HIC1 re-expression or siRNA-mediated ADRB2 knockdown. Promoter luciferase assay, ChIP, sequential ChIP, siRNA knockdown, migration and invasion assays The Journal of biological chemistry Medium 22194601
2012 HIC1 interacts with Polycomb-like proteins hPCL3 and PHF1 to form a stable complex with PRC2 members EZH2, EED, and Suz12; this complex represses HIC1 target genes including ATOH1; HIC1 siRNA knockdown leads to partial displacement of EZH2 from the ATOH1 promoter. Yeast two-hybrid, co-immunoprecipitation, ChIP, siRNA knockdown, in vivo mouse cerebellar developmental model The Journal of biological chemistry High 22315224
2013 DNA double-strand breaks activate HIC1 SUMOylation on K314 through a mechanism involving enhanced HDAC4/Ubc9 interaction, SUMOylation of SIRT1 (Lys-734), and SUMO-dependent recruitment of HDAC4 by SIRT1. This deacetylation/SUMOylation switch of HIC1 favors HIC1/MTA1 interaction and promotes DNA repair. Wild-type but not non-SUMOylatable HIC1 mutants reduce γH2AX foci after etoposide treatment. Co-immunoprecipitation, in vivo SUMOylation assay, γH2AX foci assay (immunofluorescence), etoposide DNA damage model, siRNA knockdown The Journal of biological chemistry Medium 23417673
2008 HIC1 recruits BRG1, the ATPase subunit of SWI/SNF chromatin-remodeling complexes, to E2F-responsive gene promoters to repress their transcription; HIC1-mediated transcriptional repression of E2F-responsive genes is dependent on BRG1 activity. ChIP, reporter assays, co-immunoprecipitation, BRG1-deficient cell lines Oncogene Medium 19015639
2004 HIC1 is O-GlcNAc glycosylated in vivo and in vitro at three major sites preferentially in the DNA-binding domain; O-GlcNAc modification does not affect the specific DNA-binding activity of full-length HIC1, but in BTB/POZ-deleted N-terminal truncations, glycosylation of the C-terminal tail (residues 670-711) abolishes DNA binding. In vivo and in vitro O-GlcNAc labeling, wheat germ agglutinin affinity purification, EMSA, C-terminal deletion mutants European journal of biochemistry Medium 15373830
2006 The L225A mutation in the HIC1 GLDLSKK motif abolishes interaction with CtBP1 and CtBP2; the CtBP interaction is stimulated by agents that increase NADH levels; loss of CtBP interaction impairs HIC1-mediated transcriptional repression. Point mutagenesis, co-immunoprecipitation, NADH/redox modulation assays, reporter transcription assays The FEBS journal Medium 16762039
2012 HIC1 forms complexes with STAT3 through interaction of the HIC1 C-terminal domain with the STAT3 DNA-binding domain; HIC1 overexpression or depletion respectively decreases or increases IL-6/OSM-induced STAT3 target gene expression (VEGF, c-Myc); HIC1 suppresses STAT3 binding to target gene promoters. Affinity capture followed by mass spectrometry, co-immunoprecipitation, luciferase reporter assays, ChIP, domain mapping, HIC1 mutant defective in STAT3 interaction Cell cycle (Georgetown, Tex.) Medium 24067369
2012 SIRT1 interacts with the BTB/POZ domain of HIC1; the amino acids 610-677 of SIRT1 (ESA region) are essential for the HIC1/SIRT1 interaction and HIC1 deacetylation; CKII-mediated phosphorylation of SIRT1 serine 659/661 (occurring upon DNA damage) is required for this interaction. Co-immunoprecipitation with deletion/domain mapping, site-directed mutagenesis, kinase assays Biochemical and biophysical research communications Medium 22510409
2015 HIC1 directly represses TLR2 transcription; ChIP shows HIC1 association with TLR2 gene regulatory elements; Hic1-deficient MEFs and intestinal organoids show increased TLR2, and Hic1 deficiency promotes NF-κB pathway activity and increases colonic tumor size in chemical carcinogenesis models. Chromatin immunoprecipitation (ChIP), conditional Cre/loxP knockout, qRT-PCR, intestinal organoid culture, in vivo carcinogenesis model Molecular cancer research : MCR Medium 25934696
2013 HIC1 directly represses p21 (CIP1/WAF1) transcription; ChIP demonstrates HIC1 occupancy on the p21 promoter; siRNA knockdown of HIC1 in BJ-Tert fibroblasts upregulates p21 and potentiates p21 response to etoposide-induced DNA damage. Luciferase promoter reporter assay, ChIP, siRNA knockdown, Western blot Biochemical and biophysical research communications Medium 23178572
2017 HIC1 SUMOylation is dispensable for DNA repair (non-SUMOylatable E316A mutant repairs DSBs as efficiently as wt HIC1 in Comet assays) but is essential for the apoptotic transcriptional response to irreparable DSBs; irreparable DSBs (but not repairable ones) increase HIC1 SUMOylation and its interaction with MTA1/MTA3 and their binding to the SIRT1 promoter via an ATM-dependent (Chk2-independent) mechanism. Comet assay, γH2AX foci assay, Co-immunoprecipitation, ChIP, site-directed mutagenesis (E316A), ATM/Chk2 inhibitors, global expression profiling Oncotarget Medium 27935866
2016 HIC1 physically interacts with CTIP2 (Bcl11b) and HMGA1 to co-regulate cellular genes and repress Tat-dependent HIV-1 transcription; this repression is linked to HIC1 K314 acetylation status and SIRT1 deacetylase activity; HIC1 cooperates with HMGA1 in a TAR-dependent manner to facilitate HIC1/TAT interaction at the viral promoter. Co-immunoprecipitation, reporter assays, K314 acetylation-status manipulation, SIRT1 activity assays Scientific reports Medium 27725726
2018 HIC1 expression in intestinal T cells is regulated by the vitamin A metabolite retinoic acid; HIC1-deficient T cells overproduce IL-17A in vitro and in vivo; T-cell-specific deletion of HIC1 reduces T cell numbers in the intestinal lamina propria and impairs intestinal immune homeostasis. Conditional T-cell-specific knockout (Cre/loxP), vitamin A-deficient diet model, flow cytometry, in vitro cytokine assays, in vivo infection model Mucosal immunology Medium 28327618
2018 HIC1-deleted breast cancer cells secrete CXCL14, which binds GPR85 on mammary fibroblasts, activating them via ERK1/2, Akt, and neddylation pathways; activated fibroblasts then promote breast cancer progression via CCL17/CCR4-induced EMT. Conditional mammary-gland-specific Hic1 knockout mouse, cytokine secretion analysis, receptor binding assays, co-culture experiments, signaling pathway inhibition The Journal of clinical investigation Medium 30204129
2019 HIC1 marks quiescent mesenchymal progenitors in skeletal muscle; Hic1 deletion leads to mesenchymal progenitor hyperplasia; single-cell RNA-seq and ATAC-seq reveal multiple subpopulations with distinct functions; Hic1+ MPs contribute to immunomodulation, trophic support, and differentiation into Col22a1-expressing myotendinous junction cells during muscle regeneration. Conditional knockout (Cre/loxP), single-cell RNA-seq, ATAC-seq, lineage tracing, flow cytometry, histology Cell stem cell High 31809738
2020 Lineage-specific deletion of HIC1 in cardiac PDGFRa+/SCA-1+ fibro/adipogenic progenitors causes fibrofatty infiltration within the myocardium and drives pathological features of arrhythmogenic cardiomyopathy, demonstrating that HIC1 maintains progenitor quiescence in the heart. Conditional Cre/loxP knockout (lineage-specific), histology, cardiac function measurement, in vitro differentiation assays Cell stem cell Medium 31978365
2016 HIC1 directly represses IL-6 transcription in non-small cell lung cancer cells through sequence-specific binding to the IL-6 promoter; loss of HIC1 induces autocrine IL-6 secretion that activates STAT3 via JAK pathway, promoting NSCLC invasion and migration. ChIP, luciferase reporter assay, siRNA knockdown, IL-6 rescue experiment, in vitro and in vivo assays Oncotarget Medium 27107418
2021 HIC1 represses Atoh1 transcription in cochlear supporting cells; Hic1 knockdown induces Atoh1 expression and promotes hair cell differentiation in cochlear organoids; wild-type HIC1 but not the DNA-binding mutant C521S suppresses the Atoh1 autoregulatory enhancer and blocks its responsiveness to β-catenin activation. siRNA knockdown and overexpression in cochlear organoids, luciferase reporter assay with Atoh1 enhancer, DNA-binding domain mutant (C521S), qRT-PCR Stem cell reports Medium 33770497
2020 In Xenopus, Hic1 regulates cranial neural crest migration by modulating cadherin expression profiles and canonical Wnt signaling; both overexpression and knockdown of hic1 impair neural crest migration in vivo and in tissue explants without affecting neural crest specification. Xenopus morpholino knockdown and mRNA overexpression, in vivo neural crest migration assay, tissue explant migration, qRT-PCR for cadherins and Wnt targets Developmental biology Medium 32502469
2021 FBXW11 targets HIC1 for ubiquitination and proteasomal degradation, reducing HIC1 protein stability in colorectal cancer cells; this leads to upregulation of SIRT1 (a direct HIC1 transcriptional target), promoting colorectal cancer stem-cell features and liver metastasis. Co-immunoprecipitation, ubiquitination assay, Western blot, siRNA knockdown, xenograft mouse model Cell death & disease Medium 34642302
2023 HIC1 directly represses GPX4 transcription in colon cancer cells; HIC1 overexpression augments ferroptotic cell death by reducing GPX4 expression, and HIC1 silencing attenuates ferroptosis and restores GPX4 expression. HIC1 overexpression/siRNA knockdown, GPX4 promoter reporter assay, glutathione and lipid peroxidation assays, xenograft model Free radical biology & medicine Low 37717793
2018 HIC1 in renal tubular epithelial cells represses SIRT1 transcription by recruiting EZH2 (H3K27 trimethyltransferase) and DNMT1 to the SIRT1 promoter in response to high glucose; this epigenetic repression of SIRT1 by HIC1 contributes to ROS accumulation. ChIP for H3K27me3 and 5-methylcytosine, Co-immunoprecipitation (HIC1 with EZH2/DNMT1), siRNA knockdown, ROS measurement Biochimica et biophysica acta. Gene regulatory mechanisms Medium 30496037

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 545 16269335
1995 p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nature medicine 394 7585125
2003 Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome. Molecular cancer 179 12773202
2003 Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nature genetics 174 12539045
2019 Hic1 Defines Quiescent Mesenchymal Progenitor Subpopulations with Distinct Functions and Fates in Skeletal Muscle Regeneration. Cell stem cell 163 31809738
2007 Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex. Proceedings of the National Academy of Sciences of the United States of America 152 17213307
2004 Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer cell 135 15488761
2007 An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Molecular and cellular biology 132 17283066
1998 Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer. Oncogene 128 9572497
2000 Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome. Human molecular genetics 111 10655551
2008 Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma. Genes & development 98 18347096
1999 Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B. Proceedings of the National Academy of Sciences of the United States of America 98 10611298
1999 DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology (Baltimore, Md.) 93 10051471
1997 HIC1 hypermethylation is a late event in hematopoietic neoplasms. Cancer research 93 9135007
2002 Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma. Cancer research 92 12097291
2002 The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. Molecular and cellular biology 87 12052894
2009 Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. Neoplasia (New York, N.Y.) 83 19649206
2006 HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies. The EMBO journal 80 16724116
2008 HIC1 (Hypermethylated in Cancer 1) epigenetic silencing in tumors. The international journal of biochemistry & cell biology 76 18723112
2004 The tumor suppressor gene HIC1 (hypermethylated in cancer 1) is a sequence-specific transcriptional repressor: definition of its consensus binding sequence and analysis of its DNA binding and repressive properties. The Journal of biological chemistry 76 15231840
2018 HIC1 deletion promotes breast cancer progression by activating tumor cell/fibroblast crosstalk. The Journal of clinical investigation 74 30204129
2010 Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells. Molecular and cellular biology 74 20547755
2000 Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53. The Journal of biological chemistry 67 11073960
2020 Pathogenic Potential of Hic1-Expressing Cardiac Stromal Progenitors. Cell stem cell 66 31978365
2009 Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target gene of HIC1 (hypermethylated in cancer 1). The Journal of biological chemistry 64 19525223
2020 Detection of aberrant methylation of HOXA9 and HIC1 through multiplex MethyLight assay in serum DNA for the early detection of epithelial ovarian cancer. International journal of cancer 55 32191343
2005 Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas. Endocrine-related cancer 55 15788647
2023 Luteolin exhibits synergistic therapeutic efficacy with erastin to induce ferroptosis in colon cancer cells through the HIC1-mediated inhibition of GPX4 expression. Free radical biology & medicine 52 37717793
2013 HIC1 silencing in triple-negative breast cancer drives progression through misregulation of LCN2. Cancer research 52 24295734
2018 Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells. Cell reports 51 29466736
2018 Hypermethylated in cancer 1 (HIC1) mediates high glucose induced ROS accumulation in renal tubular epithelial cells by epigenetically repressing SIRT1 transcription. Biochimica et biophysica acta. Gene regulatory mechanisms 51 30496037
2013 HIC1 modulates prostate cancer progression by epigenetic modification. Clinical cancer research : an official journal of the American Association for Cancer Research 51 23340301
1999 Cancer-specific region of hypermethylation identified within the HIC1 putative tumour suppressor gene in acute myeloid leukaemia. Leukemia 48 10360376
2003 Epigenetic silencing of the HIC-1 gene in human medulloblastomas. Journal of neuropathology and experimental neurology 47 14656076
1999 Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome. Human molecular genetics 47 10072440
2003 Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clinical cancer research : an official journal of the American Association for Cancer Research 45 14506157
2009 HIC1 interacts with a specific subunit of SWI/SNF complexes, ARID1A/BAF250A. Biochemical and biophysical research communications 44 19486893
2004 Analysis of HIC-1 methylation and transcription in human ependymomas. International journal of cancer 44 15122586
2012 Hypermethylated in cancer 1 (HIC1) recruits polycomb repressive complex 2 (PRC2) to a subset of its target genes through interaction with human polycomb-like (hPCL) proteins. The Journal of biological chemistry 41 22315224
2012 Hypermethylated in cancer 1 (HIC1), a tumor suppressor gene epigenetically deregulated in hyperparathyroid tumors by histone H3 lysine modification. The Journal of clinical endocrinology and metabolism 39 22544915
2010 A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1. Oncogene 39 20154726
2013 DNA double-strand breaks lead to activation of hypermethylated in cancer 1 (HIC1) by SUMOylation to regulate DNA repair. The Journal of biological chemistry 37 23417673
2013 Deciphering HIC1 control pathways to reveal new avenues in cancer therapeutics. Expert opinion on therapeutic targets 37 23566242
2017 The transcriptional repressor HIC1 regulates intestinal immune homeostasis. Mucosal immunology 36 28327618
2001 Expression of the Hypermethylated in Cancer gene (HIC-1) is associated with good outcome in human breast cancer. British journal of cancer 36 11747329
2021 FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer. Cell death & disease 35 34642302
2016 HIC1 attenuates invasion and metastasis by inhibiting the IL-6/STAT3 signalling pathway in human pancreatic cancer. Cancer letters 34 27085461
2016 HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer. Cell death and differentiation 34 28009350
2021 Serum exosomes from diabetic kidney disease patients promote pyroptosis and oxidative stress through the miR-4449/HIC1 pathway. Nutrition & diabetes 33 34732690
2012 Hypermethylation of HIC1 promoter and aberrant expression of HIC1/SIRT1 might contribute to the carcinogenesis of pancreatic cancer. Annals of surgical oncology 33 22552606
2016 KRAS, BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2, DAPK1, MGMT, HIC1 and p16 genes in colorectal cancer patients. Cancer biomarkers : section A of Disease markers 32 27540971
2001 Characterization of HRG22, a human homologue of the putative tumor suppressor gene HIC1. Biochemical and biophysical research communications 32 11554746
2011 Promoter hypermethylation of RASSF1A, MGMT, and HIC-1 genes in benign and malignant colorectal tumors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 31 21274674
2011 The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). The Journal of biological chemistry 30 22184117
2008 HIC1 tumour suppressor gene is suppressed in acute myeloid leukaemia and induced during granulocytic differentiation. British journal of haematology 30 18318772
2015 HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage-Associated Tumorigenesis. Molecular cancer research : MCR 28 25934696
2011 Loss of Hypermethylated in Cancer 1 (HIC1) in breast cancer cells contributes to stress-induced migration and invasion through β-2 adrenergic receptor (ADRB2) misregulation. The Journal of biological chemistry 27 22194601
2018 The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53. Oncogene 26 29367758
2017 HIC1 loss promotes prostate cancer metastasis by triggering epithelial-mesenchymal transition. The Journal of pathology 26 28466555
2016 HIC1 controls cellular- and HIV-1- gene transcription via interactions with CTIP2 and HMGA1. Scientific reports 26 27725726
2012 Signification of Hypermethylated in Cancer 1 (HIC1) as Tumor Suppressor Gene in Tumor Progression. Cancer microenvironment : official journal of the International Cancer Microenvironment Society 26 22528874
2004 The tumor suppressor HIC1 (hypermethylated in cancer 1) is O-GlcNAc glycosylated. European journal of biochemistry 26 15373830
2022 Cellular taxonomy of Hic1+ mesenchymal progenitor derivatives in the limb: from embryo to adult. Nature communications 25 36008423
2011 Loss of a single Hic1 allele accelerates polyp formation in Apc(Δ716) mice. Oncogene 24 21297660
2019 Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer. BMC cancer 23 31795965
2011 Identification of novel subregions of LOH in gastric cancer and analysis of the HIC1 and TOB1 tumor suppressor genes in these subregions. Molecules and cells 23 21533545
2016 Hypermethylation of the HIC1 promoter and aberrant expression of HIC1/SIRT1 contribute to the development of thyroid papillary carcinoma. Oncotarget 22 27793057
2007 Detailed mapping of chromosome 17p deletions reveals HIC1 as a novel tumor suppressor gene candidate telomeric to TP53 in diffuse large B-cell lymphoma. Oncogene 22 17982487
2005 HIC1 promoter methylation and 17p13.3 allelic loss in invasive ductal carcinoma of the breast. Cancer letters 22 15837543
2015 Epigenetic silencing of HIC1 promotes epithelial-mesenchymal transition and drives progression in esophageal squamous cell carcinoma. Oncotarget 21 26510908
2011 Alterations in promoter methylation status of tumor suppressor HIC1, SFRP2, and DAPK1 genes in prostate carcinomas. DNA and cell biology 21 22136354
2010 Demethylation treatment restores hic1 expression and impairs aggressiveness of head and neck squamous cell carcinoma. Oral oncology 21 20729134
2011 Generation of two modified mouse alleles of the Hic1 tumor suppressor gene. Genesis (New York, N.Y. : 2000) 20 21309068
2008 Just say no to ATOH: how HIC1 methylation might predispose medulloblastoma to lineage addiction. Cancer research 19 18974104
2016 HIC1 modulates uveal melanoma progression by activating lncRNA-numb. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 18 27449031
2013 HIC1 interacts with and modulates the activity of STAT3. Cell cycle (Georgetown, Tex.) 18 24067369
2008 Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control. Oncogene 18 19015639
1998 The carboxy-terminal end of the candidate tumor suppressor gene HIC-1 is phylogenetically conserved. Biochimica et biophysica acta 18 9838134
2018 HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis. PLoS pathogens 17 29470558
2010 Gene methylation of SFRP2, P16, DAPK1, HIC1, and MGMT and KRAS mutations in sporadic colorectal cancer. Cancer genetics and cytogenetics 17 20682398
2004 Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1. Oncogene 17 15007385
2016 Hypermethylated in cancer 1(HIC1) suppresses non-small cell lung cancer progression by targeting interleukin-6/Stat3 pathway. Oncotarget 16 27107418
2012 Identification of p21 (CIP1/WAF1) as a direct target gene of HIC1 (Hypermethylated In Cancer 1). Biochemical and biophysical research communications 16 23178572
2009 Implication of HIC1 (Hypermethylated In Cancer 1) in the DNA damage response. Bulletin du cancer 16 19822477
2013 Methylation pattern of THBS1, GATA-4, and HIC1 in pediatric and adult patients infected with Helicobacter pylori. Digestive diseases and sciences 15 23765259
2006 A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor CtBP. The FEBS journal 15 16762039
2020 Development and function of smooth muscle cells is modulated by Hic1 in mouse testis. Development (Cambridge, England) 14 32554530
2014 P53 induction accompanying G2/M arrest upon knockdown of tumor suppressor HIC1 in U87MG glioma cells. Molecular and cellular biochemistry 14 24992983
2008 Lipopolysaccharide induces aberrant hypermethylation of Hic-1 in mouse embryonic fibroblasts lacking p53 gene. Anticancer research 14 18751382
2018 Wnt Secretion Is Regulated by the Tetraspan Protein HIC-1 through Its Interaction with Neurabin/NAB-1. Cell reports 13 30428353
2013 Inactivation of tumor suppressor gene HIC1 in gastric cancer is reversed via small activating RNAs. Gene 13 23769968
2022 ZBTB7A, a miR-144-3p targeted gene, accelerates bladder cancer progression via downregulating HIC1 expression. Cancer cell international 12 35501800
2019 miR-128 Functions as an OncomiR for the Downregulation of HIC1 in Breast Cancer. Frontiers in pharmacology 12 31680974
2006 Identification and functional characterization of a novel unspliced transcript variant of HIC-1 in human cancer cells exposed to adverse growth conditions. Cancer research 12 17079468
2004 Identification and developmental expression of the zebrafish orthologue of the tumor suppressor gene HIC1. Biochimica et biophysica acta 12 15093138
2021 HIC1 Represses Atoh1 Transcription and Hair Cell Differentiation in the Cochlea. Stem cell reports 11 33770497
2020 The transcription factor Hypermethylated in Cancer 1 (Hic1) regulates neural crest migration via interaction with Wnt signaling. Developmental biology 11 32502469
2017 HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs). Oncotarget 11 27935866
2014 Small activating RNA restores the activity of the tumor suppressor HIC-1 on breast cancer. PloS one 11 24489730
2012 Molecular dissection of the interaction between HIC1 and SIRT1. Biochemical and biophysical research communications 11 22510409

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