Affinage

SETD2

Histone-lysine N-methyltransferase SETD2 · UniProt Q9BYW2

Length
2564 aa
Mass
287.6 kDa
Annotated
2026-06-10
100 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SETD2 (HYPB) is the principal mammalian histone H3K36 trimethyltransferase, responsible for virtually all global and transcription-coupled H3K36me3 while leaving H3K36 mono- and dimethylation intact (PMID:18157086). It is recruited co-transcriptionally to the RNA polymerase II elongation complex through an IWS1–SPT6 bridge that engages the Pol II CTD, and cryo-EM of the mammalian elongation machinery shows SETD2 positioned to methylate H3K36 on both downstream and upstream nucleosomes, with the SPT6 death-like domain making a direct contact when SETD2 acts on the upstream nucleosome (PMID:19141475, PMID:39666822). Through this activity SETD2 enforces correct chromatin dynamics during elongation: H3K36me3 coordinates FACT (SPT16/SSRP1) recruitment and nucleosome/H2B exchange to suppress cryptic intragenic transcription (PMID:23325844), and SETD2 loss couples epigenome disruption to transcriptome dysregulation, producing DNA hypermethylation and ectopic gains of repressive marks (PMID:26646321). The same elongation-linked mark governs developmental programs, including V(D)J recombination, where H3K36me3 at the TCRβ locus licenses RAG1 binding so that Setd2 loss arrests thymocyte and B-cell development (PMID:31350389), and immune-cell fate, where H3K36me3 sustains GATA3 and Il1rl1 expression in tissue Treg cells (PMID:36463230). Beyond histones, SETD2 has non-histone substrates: it trimethylates EZH2 to drive its degradation and restrain H3K27me3 (PMID:32619406), and within a SETD2–HTT–HIP1R complex it trimethylates actin lysine-68 to regulate F-actin polymerization and cell migration (PMID:33008892), the latter mediated by an autoinhibited WW domain that interacts with the huntingtin proline-rich region (PMID:24412394). Loss of SETD2 acts as a tumor suppressor across diverse cancers, driving replication stress and myelodysplasia in hematopoietic stem cells (PMID:29531312), KRAS-driven pancreatic metaplasia and immune escape (PMID:31300513, PMID:36453584), and renal tumorigenesis linked to metabolic reprogramming (PMID:37989747), establishing SETD2 as an integrator of transcription, chromatin, splicing, cytoskeletal regulation, and tumor suppression.

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2007 High

    Established which enzyme deposits H3K36me3 in mammals, resolving the source of the transcription-associated trimethyl mark versus lower methylation states.

    Evidence siRNA knockdown of HYPB/Setd2 in murine fibroblasts with high-resolution ChIP across induced c-fos/c-jun

    PMID:18157086

    Open questions at the time
    • Did not define how SETD2 is targeted to transcribed genes
    • Mechanism distinguishing me3 from me1/me2 deposition unresolved
  2. 2008 High

    Answered how SETD2 reaches active gene bodies by identifying the IWS1–SPT6 bridge to elongating Pol II, and linked the enzyme to mRNA export.

    Evidence Reciprocal Co-IP, siRNA knockdown of Iws1/SETD2 with ChIP, in vitro Spt6–CTD binding across multiple genes

    PMID:19141475

    Open questions at the time
    • Structural basis of the megacomplex not resolved
    • Mechanism connecting H3K36me3 to poly(A)+ mRNA export not defined
  3. 2010 High

    Demonstrated the physiological requirement for SETD2/H3K36me3 in vivo through embryonic lethality with vascular and migration defects.

    Evidence Conditional Setd2 knockout mice, tetraploid rescue, IF, endothelial migration/invasion assays

    PMID:20133625

    Open questions at the time
    • Did not pinpoint the H3K36me3 target genes driving vascular defects
    • Cell-migration link to a direct molecular mechanism not established at this stage
  4. 2013 High

    Mechanistically connected H3K36me3 to suppression of cryptic transcription via FACT-dependent nucleosome dynamics during elongation.

    Evidence siRNA knockdown with RNA-seq for cryptic initiation, nucleosome/H2B ChIP, SPT16 Co-IP, live imaging

    PMID:23325844

    Open questions at the time
    • Direct biochemical reader linking H3K36me3 to FACT recruitment not isolated
    • Single-lab observation
  5. 2016 Medium

    Showed SETD2 loss couples epigenome and transcriptome disruption by producing DNA hypermethylation and ectopic H3K36me3 gains, generalizable across tumor types.

    Evidence Genome-wide methylation arrays and H3K36me3 ChIP-seq in cell models plus primary RCC and lung tumors

    PMID:26646321

    Open questions at the time
    • Causal mechanism linking H3K36me3 loss to DNA hypermethylation not fully resolved
    • Single lab
  6. 2017 Medium

    Revealed crosstalk between the SETD2-H3K36me3 axis and the DOT1L-H3K79me2 axis in leukemia, expanding how SETD2 loss deregulates oncogenes and tumor suppressors.

    Evidence H3K36me3/H3K79me2 ChIP-seq and RNA-seq in SETD2-inactivated leukemia cells with patient samples

    PMID:29249820

    Open questions at the time
    • Molecular basis of H3K79me2 elevation upon H3K36me3 loss not defined
    • Single lab
  7. 2018 High

    Defined a tumor-suppressive role in hematopoiesis, showing SETD2 loss induces replication stress and progresses to MDS-like malignancy.

    Evidence Conditional Setd2 KO mice, serial bone-marrow transplantation, expression profiling, cell-cycle analysis

    PMID:29531312

    Open questions at the time
    • Direct H3K36me3 targets driving replication stress not pinpointed
    • Overlap with Dnmt3a/Tet2 pathways only partial
  8. 2019 High

    Identified SETD2 as a tumor suppressor in KRAS-driven pancreatic carcinogenesis acting through H3K36me3-dependent regulation of specific loci.

    Evidence PdxCre Setd2 flox × KrasG12D mice, CRISPR depletion in PDAC cells, H3K36me3 ChIP-seq and RNA-seq

    PMID:31300513

    Open questions at the time
    • Relative contribution of Fbxw7, Ctnna1, and Akt arms not dissected
    • Mechanism of sustained Akt activation via ECM incompletely defined
  9. 2019 High

    Showed H3K36me3 directly licenses antigen-receptor recombination by enabling RAG1 binding, explaining lymphocyte developmental arrest upon SETD2 loss.

    Evidence Conditional Setd2 KO mice, H3K36me3 and RAG1 ChIP at TCRβ, flow cytometry, DSB repair assays

    PMID:31350389

    Open questions at the time
    • Whether RAG1 directly reads H3K36me3 or requires a reader not established
    • Generality across all antigen-receptor loci not exhaustively mapped
  10. 2020 High

    Identified the first non-histone protein substrate, EZH2, defining a methylation-degradation circuit that restrains H3K27me3 and metastasis, with metabolic input via AMPK-FOXO3.

    Evidence Co-IP, in vitro methyltransferase assay, knock-in mice with nonmethylatable EZH2 and EZH2-binding-defective SETD2, H3K27me3 ChIP-seq

    PMID:32619406

    Open questions at the time
    • The EZH2 lysine site and degradation machinery details not fully specified here
    • Tissue scope of the EZH2 axis beyond prostate not defined
  11. 2020 High

    Extended SETD2 catalytic scope to the cytoskeleton, showing it trimethylates actin K68 within a HTT-HIP1R complex to control polymerization and migration.

    Evidence Co-IP of SETD2-HTT-HIP1R, in vitro methyltransferase assay on purified actin, MS site identification, polymerization and migration assays

    PMID:33008892

    Open questions at the time
    • Subcellular pool of SETD2 performing actin methylation not delineated
    • Single lab
  12. 2020 High

    Provided a structural basis for SETD2 regulation, showing an autoinhibited WW domain governing the huntingtin interaction.

    Evidence NMR structure of WW–polyproline complex, chemical shift perturbation, IF co-localization

    PMID:24412394

    Open questions at the time
    • How autoinhibition is relieved in cells not defined
    • Functional consequence for catalysis not directly tested
  13. 2020 Medium

    Implicated SETD2 in alternative splicing control, linking its loss to defective ATG12 conjugation and reduced autophagic flux in RCC.

    Evidence SETD2 rescue/knockdown in RCC cells, western blot of ATG12 complexes, RT-PCR isoforms, autophagy flux assays

    PMID:31988284

    Open questions at the time
    • Direct link from H3K36me3 to ATG12 splicing not mechanistically demonstrated
    • Single lab
  14. 2022 Medium

    Connected SETD2 loss to tumor immune escape via H3K27me3-mediated Cxadr silencing, PI3K-AKT activation, and immunosuppressive neutrophil reprogramming.

    Evidence Setd2 conditional KO mice, immune profiling, H3K27me3/H3K36me3 ChIP-seq at Cxadr, cytokine assays, neutrophil–CD8 co-culture

    PMID:36453584

    Open questions at the time
    • Mechanism converting H3K36me3 loss to H3K27me3 gain at Cxadr not detailed
    • Single lab
  15. 2022 Medium

    Showed SETD2 sustains tissue Treg identity and suppressive function through H3K36me3 at GATA3 and Il1rl1 regulatory elements.

    Evidence Foxp3Cre Setd2 KO mice, H3K36me3 ChIP-seq, flow cytometry, IL-33 stimulation, human Treg knockdown

    PMID:36463230

    Open questions at the time
    • Whether GATA3/Il1rl1 are direct primary targets vs downstream effects not fully resolved
    • Single lab
  16. 2023 Medium

    Linked SETD2 deficiency to metabolic reprogramming, identifying sphingomyelin biosynthesis as a causal, druggable driver of renal tumor transition.

    Evidence Conditional Setd2 KO PKD-ccRCC mice, multi-omics, myriocin pharmacological rescue, patient validation

    PMID:37989747

    Open questions at the time
    • Direct chromatin targets controlling sphingolipid genes not pinpointed
    • Single lab
  17. 2024 High

    Resolved the structural architecture of SETD2 within the Pol II elongation complex, explaining how it accesses both upstream and downstream nucleosomes via SPT6.

    Evidence Cryo-EM of mammalian Pol II–DSIF–SPT6–PAF1c–TFIIS–IWS1–SETD2–nucleosome complexes

    PMID:39666822

    Open questions at the time
    • Catalytic conformational cycle during translocation not captured
    • Regulation of SETD2 dwell time per nucleosome unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SETD2 substrate selection (histone H3K36 vs EZH2 vs actin) is partitioned across cellular compartments and signaling states remains unresolved.
  • No unifying model for how one enzyme selects histone vs non-histone substrates
  • Compartment-specific regulation of catalytic activity not defined
  • Direct readers translating H3K36me3 to DNA methylation and splicing outcomes incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0042393 histone binding 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2
Partners
EZH2HIP1RHTTIWS1RAG1SPT16SPT6
Complex memberships
RNA Pol II elongation complex (with IWS1-SPT6)SETD2-HTT-HIP1R complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 HYPB/SETD2 is responsible for virtually all global and transcription-dependent H3K36 trimethylation (H3K36me3) in mammalian cells, but not H3K36 mono- or dimethylation. This was demonstrated by knockdown of HYPB/Setd2 in murine fibroblasts, which abolished H3K36me3 across c-fos and c-jun coding regions upon gene induction. siRNA knockdown of HYPB/Setd2 in murine fibroblasts combined with high-resolution ChIP mapping of histone modifications The EMBO journal High 18157086
2008 IWS1 (Iws1) recruits HYPB/SETD2 to the RNA polymerase II elongation complex via Spt6, and this recruitment is required for H3K36me3 across transcribed gene bodies. Knockdown of HYPB/SETD2 also caused nuclear accumulation of poly(A)+ mRNAs, indicating a role in mRNA export. Spt6 binds the CTD N-terminal consensus repeats and recruits Iws1, which bridges to HYPB/SETD2, forming a megacomplex. Co-immunoprecipitation, siRNA knockdown of Iws1 and HYPB/Setd2, ChIP for H3K36me3 across c-Myc, HIV-1, PABPC1 genes; in vitro binding assay (recombinant Spt6 binding to CTD) Genes & development High 19141475
2010 Homozygous knockout of Hypb/Setd2 in mice impairs H3K36 trimethylation (but not mono- or dimethylation) and causes embryonic lethality at E10.5–E11.5 with severe vascular remodeling defects. Hypb-deficient endothelial cells and embryonic bodies showed defects in cell migration and invasion, establishing an intrinsic role for Hypb in vascular development. Conditional knockout mouse model, immunofluorescence for histone modifications, tetraploid rescue experiment, siRNA knockdown in human endothelial cells, in vitro migration/invasion assays Proceedings of the National Academy of Sciences of the United States of America High 20133625
2013 SETD2 downregulation in human cells leads to intragenic (cryptic) transcription initiation at ~11% of active genes. SETD2 coordinates FACT complex (SPT16/SSRP1) recruitment to H3K36me3-containing nucleosomes and regulates nucleosome occupancy and histone H2B exchange during transcription elongation. Co-immunoprecipitation showed SPT16 associates with H3K36me3-containing chromatin. siRNA knockdown of SETD2 in human cells, RNA-seq for cryptic transcription, ChIP for nucleosome occupancy and H2B/H3, co-immunoprecipitation of SPT16 with H3K36me3 chromatin, live-cell imaging with transcription inhibition Nucleic acids research High 23325844
2014 The WW domain of HYPB/SETD2 adopts an autoinhibitory closed conformation due to intramolecular binding of a C-terminal polyproline stretch to the WW core domain. This autoinhibitory structure regulates interaction between the HYPB WW domain and the proline-rich region (PRR) of huntingtin (Htt), as shown by NMR solution structure and immunofluorescence. NMR structure determination of the WW domain–polyproline complex, NMR chemical shift perturbation, immunofluorescence co-localization assays Structure (London, England : 1993) High 24412394
2016 SETD2 inactivation in human cells drives a DNA hypermethylation phenotype with ectopic gains of H3K36me3 centered on intergenic regions adjacent to low-expressing genes, and poised enhancers of developmental genes are prominent hypermethylation targets. SETD2 mutant primary ccRCC, papillary RCC, and lung adenocarcinomas all show this hypermethylation phenotype, demonstrating that SETD2 mutations coordinate disruption of both the epigenome and transcriptome. Genome-wide DNA methylation profiling (array), ChIP-seq for H3K36me3, cell line-based SETD2 inactivation models (long-term and acute), primary tumor analysis Oncotarget Medium 26646321
2017 In MLL-rearranged leukemia, SETD2 inactivation leads to global reduction of H3K36me3 and further elevation of H3K79me2, revealing a crosstalk between the SETD2-H3K36me3 axis and the DOT1L-H3K79me2 axis that deregulates tumor suppressors (e.g., ASXL1) and oncogenes (e.g., ERG) independently of canonical MLL fusion targets. ChIP-seq for H3K36me3 and H3K79me2, RNA-seq in SETD2-inactivated leukemia cells, patient sample analysis Leukemia Medium 29249820
2018 Setd2 deficiency in hematopoietic stem cells (HSCs) impairs self-renewal and competitive fitness, induces DNA replication stress (evidenced by activated E2F network and repressed Rrm2b expression), and eventually leads to myelodysplastic syndrome-like malignancy. Gene expression profiles of Setd2-deleted HSPCs partially overlap with Dnmt3a/Tet2 double-KO HSPCs, with activation of the Klf1-related erythroid pathway. Conditional Setd2 knockout mice, serial bone marrow transplantation, gene expression profiling, cell cycle analysis Cell research High 29531312
2019 Setd2 acts as a tumor suppressor in KRAS-driven pancreatic carcinogenesis. Setd2 loss in acinar cells facilitates KRAS-induced acinar-to-ductal metaplasia through epigenetic dysregulation of Fbxw7 (reduced H3K36me3 at Fbxw7 locus). Setd2 ablation in pancreatic cancer cells enhances EMT via impaired epigenetic regulation of Ctnna1, and leads to sustained Akt activation through ECM production. PdxCreSetd2 flox/flox × KrasG12D conditional KO mice, CRISPR/Cas9 depletion in PDAC cells, RNA-seq and H3K36me3 ChIP-seq Gut High 31300513
2019 Setd2 deficiency causes a severe developmental block of thymocytes at the DN3 stage by reducing H3K36me3 at the TCRβ locus, impairing RAG1 binding and V(D)J recombination. Similarly, Setd2 loss blocks B cell development at the pro-B stage by impairing immunoglobulin V(D)J rearrangement. Conditional Setd2 knockout mice, ChIP for H3K36me3 and RAG1 at TCRβ locus, flow cytometry for lymphocyte developmental stages, DSB repair assays Nature communications High 31350389
2020 SETD2 trimethylates EZH2 on a specific lysine, promoting EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state (increased H3K27me3) enabling cells to acquire metastatic traits in prostate cancer. Metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression, linking metabolic and epigenetic pathways. Co-immunoprecipitation, in vitro methyltransferase assay with recombinant proteins, knock-in mice with nonmethylatable EZH2 mutant and SETD2 mutant defective in EZH2 binding, H3K27me3 ChIP-seq, AMPK/FOXO3 pathway epistasis Cancer cell High 32619406
2020 SETD2 is an actin lysine methyltransferase that trimethylates lysine-68 of actin (ActK68me3) in cells via its interaction with huntingtin (HTT) and the actin-binding adapter HIP1R. ActK68me3 localizes primarily to the insoluble F-actin cytoskeleton and regulates actin polymerization/depolymerization dynamics. Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration. Co-immunoprecipitation of SETD2-HTT-HIP1R complex, in vitro methyltransferase assay with purified actin and SETD2, mass spectrometry identification of ActK68me3, actin polymerization assays, cell migration assays with SETD2 knockdown/knockout Science advances High 33008892
2020 SETD2 deficiency in renal clear cell carcinoma cells is associated with aberrant accumulation of free ATG12 and a distinct ATG12-containing complex, and with increased expression of a short ATG12 spliced isoform at the expense of the canonical long isoform. This impairs the ATG12 conjugation system and decreases autophagic flux, establishing a role for SETD2 as a regulator of alternative splicing of ATG12 and autophagy. SETD2 rescue and knockdown in RCC cells, western blot for ATG12 complexes, RT-PCR for ATG12 isoforms, autophagic flux assays Cell death & disease Medium 31988284
2022 Setd2 deficiency in pancreatic tumor cells leads to ectopic H3K27me3 gain at the Cxadr locus, downregulating Cxadr expression, which boosts PI3K-AKT signaling and excessive CXCL1 and GM-CSF secretion. This promotes recruitment and reprogramming of neutrophils toward an immunosuppressive phenotype, fostering CD8+ T cell inhibition and tumor immune escape. Setd2 conditional KO mouse model, comprehensive immune profiling of TME, H3K27me3 and H3K36me3 ChIP-seq at Cxadr locus, cytokine measurement (CXCL1, GM-CSF), neutrophil co-culture assays with CD8+ T cells Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 36453584
2022 Setd2 supports GATA3+ST2+ intestinal thymic-derived Treg cell survival and suppressive function by facilitating GATA3 and ST2 (IL1RL1) expression through H3K36me3 deposition at promoters and intragenic enhancers of target genes including Il1rl1. In human Treg cells, SETD2 sustains GATA3 expression. Foxp3Cre Setd2 conditional KO mice, H3K36me3 ChIP-seq at target gene loci, flow cytometry for Treg subsets, IL-33 stimulation assays, human Treg cell SETD2 knockdown Nature communications Medium 36463230
2023 SETD2 loss in kidneys causes extensive metabolic reprogramming including enhanced sphingomyelin biosynthesis, which promotes PKD-to-ccRCC tumor transition. Inhibition of sphingomyelin biosynthesis with myriocin relieves tumor symptoms in Setd2 knockout mice, establishing a causal mechanistic link between SETD2 deficiency and sphingolipid metabolism in renal tumorigenesis. Conditional Setd2 KO mouse model (PKD-ccRCC transition), metabolomics, lipidomics, transcriptomics, proteomics; myriocin pharmacological rescue; clinical ccRCC patient specimen validation Nature communications Medium 37989747
2024 Cryo-EM structures of mammalian RNA Pol II–DSIF–SPT6–PAF1c–TFIIS–IWS1–SETD2–nucleosome elongation complexes reveal that SETD2 is positioned to methylate H3K36 on both downstream and upstream nucleosomes during transcription elongation. SPT6 binds the exposed H2A-H2B dimer on actively transcribed nucleosomes, and the SPT6 death-like domain mediates a direct interaction with SETD2 when it is bound to the upstream nucleosome. Cryo-electron microscopy structure determination of mammalian elongation complex with SETD2 and nucleosome Science (New York, N.Y.) High 39666822

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Targeting HIF-1 for cancer therapy. Nature reviews. Cancer 5451 13130303
2000 HIF-1: mediator of physiological and pathophysiological responses to hypoxia. Journal of applied physiology (Bethesda, Md. : 1985) 1438 10749844
2006 Hypoxia-inducible factor-1 (HIF-1). Molecular pharmacology 1320 16887934
2009 HIF-1: upstream and downstream of cancer metabolism. Current opinion in genetics & development 1082 19942427
2013 HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. The Journal of clinical investigation 1073 23999440
2001 HIF-1 and mechanisms of hypoxia sensing. Current opinion in cell biology 1022 11248550
2002 HIF-1 and tumor progression: pathophysiology and therapeutics. Trends in molecular medicine 829 11927290
2007 Hypoxia-inducible factor 1 (HIF-1) pathway. Science's STKE : signal transduction knowledge environment 733 17925579
2015 HIF-1 at the crossroads of hypoxia, inflammation, and cancer. International journal of cancer 457 25784597
2007 Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. The EMBO journal 449 18157086
2015 Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Molecular biology reports 431 25689954
2009 Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proceedings of the National Academy of Sciences of the United States of America 388 19805192
2008 HIF-1 regulation: not so easy come, easy go. Trends in biochemical sciences 279 18809331
2005 Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends in cardiovascular medicine 268 15885571
2018 Role of HIF-1 in Cancer Progression: Novel Insights. A Review. Current molecular medicine 252 30411685
2007 HIF-1 and HIF-2: working alone or together in hypoxia? The Journal of clinical investigation 232 17404612
2005 Negative and positive regulation of HIF-1: a complex network. Biochimica et biophysica acta 228 15994012
2007 HIF-1 mediates the Warburg effect in clear cell renal carcinoma. Journal of bioenergetics and biomembranes 227 17551816
2000 HIF-1: using two hands to flip the angiogenic switch. Cancer metastasis reviews 208 11191064
2008 The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. Genes & development 200 19141475
2004 Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer cell 199 15144945
2000 Hypoxia, HIF-1, and the pathophysiology of common human diseases. Advances in experimental medicine and biology 193 10849654
2004 HIF-1: an oxygen and metal responsive transcription factor. Cancer biology & therapy 191 14726713
2009 Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiation research 189 19929412
1999 HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic acids research 170 10518614
2020 SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways. Cancer cell 166 32619406
2004 HIF-1 and p53: communication of transcription factors under hypoxia. Journal of cellular and molecular medicine 150 15601571
2010 Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proceedings of the National Academy of Sciences of the United States of America 142 20133625
2007 RACK1 vs. HSP90: competition for HIF-1 alpha degradation vs. stabilization. Cell cycle (Georgetown, Tex.) 140 17361105
2013 Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription. Nucleic acids research 132 23325844
2020 Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK. Cancers 130 32252351
2004 HIF-1 and hypoxic response: the plot thickens. Current opinion in genetics & development 128 15108809
2004 New anticancer strategies targeting HIF-1. Biochemical pharmacology 128 15313402
2009 HIF-1: a key mediator in hypoxia. Acta physiologica Hungarica 125 19264039
2010 Hypoxia inducible factor 1 (HIF-1) and cardioprotection. Acta pharmacologica Sinica 124 20711226
2012 HIF-1 versus HIF-2--is one more important than the other? Vascular pharmacology 123 22366374
2016 SETD2: an epigenetic modifier with tumor suppressor functionality. Oncotarget 119 27191891
2004 HIF-1: master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs. Biochemical pharmacology 119 15313390
2007 Significance of HIF-1-active cells in angiogenesis and radioresistance. Oncogene 113 17563752
2007 Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores. Gastroenterology 112 18325389
2018 HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart. Frontiers in endocrinology 104 30158902
2007 HIF-1-dependent respiratory, cardiovascular, and redox responses to chronic intermittent hypoxia. Antioxidants & redox signaling 104 17627473
2017 Shaping the cellular landscape with Set2/SETD2 methylation. Cellular and molecular life sciences : CMLS 101 28386724
2003 HIF-1 in cell cycle regulation, apoptosis, and tumor progression. Antioxidants & redox signaling 101 13678535
2014 HIF-1 signaling in drug resistance to chemotherapy. Current medicinal chemistry 96 24735366
2004 Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Molecular and cellular biology 95 15456877
2015 HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology. Cellular and molecular life sciences : CMLS 92 26298291
2007 HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes. American journal of physiology. Endocrinology and metabolism 91 17878221
2015 BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies. Expert review of molecular diagnostics 90 26166446
2005 Hypoxia and HIF-1 alpha in chondrogenesis. Seminars in cell & developmental biology 84 16144691
2001 The pVHL-hIF-1 system. A key mediator of oxygen homeostasis. Advances in experimental medicine and biology 83 11950150
2007 HIF-1-regulated glucose metabolism: a key to apoptosis resistance? Cell cycle (Georgetown, Tex.) 79 17404504
2021 Regulation of redox signaling in HIF-1-dependent tumor angiogenesis. The FEBS journal 76 34228878
2016 Hypoxia and HIF-1 activation in bacterial infections. Microbes and infection 76 27903434
2005 Neuroprotection by hypoxic preconditioning: HIF-1 and erythropoietin protect from retinal degeneration. Seminars in cell & developmental biology 76 16144690
2021 Flavonoids Targeting HIF-1: Implications on Cancer Metabolism. Cancers 75 33401572
2021 PLAGL2-EGFR-HIF-1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity. Hepatology (Baltimore, Md.) 73 32335942
2019 HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia. BMC medical genetics 73 30808328
2019 Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis. Gut 70 31300513
2020 Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers. Journal of Cancer 69 32231741
2017 SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation. Cold Spring Harbor perspectives in medicine 69 28159833
2008 Epigenetic and HIF-1 regulation of stanniocalcin-2 expression in human cancer cells. Experimental cell research 64 18394600
2015 Modeling the interplay between the HIF-1 and p53 pathways in hypoxia. Scientific reports 63 26346319
2019 HIF-1-VEGF-Notch mediates angiogenesis in temporomandibular joint osteoarthritis. American journal of translational research 62 31217867
2019 Roles of SETD2 in Leukemia-Transcription, DNA-Damage, and Beyond. International journal of molecular sciences 60 30818762
2018 Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell research 58 29531312
2016 Melatonin and the von Hippel-Lindau/HIF-1 oxygen sensing mechanism: A review. Biochimica et biophysica acta 57 26899267
1997 The HypB protein from Bradyrhizobium japonicum can store nickel and is required for the nickel-dependent transcriptional regulation of hydrogenase. Molecular microbiology 57 9140970
2022 PBRM1, SETD2 and BAP1 - the trinity of 3p in clear cell renal cell carcinoma. Nature reviews. Urology 56 36253570
2008 HIF-1 and ventilatory acclimatization to chronic hypoxia. Respiratory physiology & neurobiology 53 18708172
2022 Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 52 36453584
2015 Temporal regulation of HIF-1 and NF-κB in hypoxic hepatocarcinoma cells. Oncotarget 51 25823824
2011 HIF-1 as a target for cancer chemotherapy, chemosensitization and chemoprevention. Current molecular pharmacology 50 20958262
2016 Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. Oncotarget 47 26646321
2011 Metallo-GTPase HypB from Helicobacter pylori and its interaction with nickel chaperone protein HypA. The Journal of biological chemistry 47 22179820
2002 ERK and calcium in activation of HIF-1. Annals of the New York Academy of Sciences 47 12485909
2007 The role of HIF-1 in hypoxic response in the skeletal muscle. Advances in experimental medicine and biology 46 18269201
2017 KDM4A regulates HIF-1 levels through H3K9me3. Scientific reports 45 28894274
2020 SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12. Cell death & disease 44 31988284
2004 Raising the bar: how HIF-1 helps determine tumor radiosensitivity. Cell cycle (Georgetown, Tex.) 44 15326390
2022 SETD2: from chromatin modifier to multipronged regulator of the genome and beyond. Cellular and molecular life sciences : CMLS 43 35661267
2020 The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase. Science advances 43 33008892
2019 The histone methyltransferase Setd2 is indispensable for V(D)J recombination. Nature communications 43 31350389
2016 The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization. Journal of molecular medicine (Berlin, Germany) 42 28004126
2003 HIF-1 alpha and VEGF expression after transient global cerebral ischemia. Advances in experimental medicine and biology 41 14562758
2014 Regulation of the VHL/HIF-1 pathway by DJ-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 24899725
2014 Autoinhibitory structure of the WW domain of HYPB/SETD2 regulates its interaction with the proline-rich region of huntingtin. Structure (London, England : 1993) 37 24412394
2022 Interaction between AhR and HIF-1 signaling pathways mediated by ARNT/HIF-1β. BMC pharmacology & toxicology 36 35473600
2020 Dimethyloxalyl Glycine Regulates the HIF-1 Signaling Pathway in Mesenchymal Stem Cells. Stem cell reviews and reports 36 32372246
2016 HIF-1--a big chapter in the cancer tale. Experimental oncology 36 27031712
2013 Metal transfer within the Escherichia coli HypB-HypA complex of hydrogenase accessory proteins. Biochemistry 35 23899293
2017 SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia. Leukemia 34 29249820
2023 SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer. Nature communications 33 37989747
2019 Transferrin receptor-involved HIF-1 signaling pathway in cervical cancer. Cancer gene therapy 33 30651591
2014 Neuroprotective effect of pAkt and HIF-1 α on ischemia rats. Asian Pacific journal of tropical medicine 33 24507644
2022 Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation. Nature communications 32 36463230
2014 HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 24558194
2023 HIF-1 signaling: an emerging mechanism for mitochondrial dynamics. Journal of physiology and biochemistry 31 37178248
2019 Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis. Oncogene 31 31043706
2024 Structural basis of H3K36 trimethylation by SETD2 during chromatin transcription. Science (New York, N.Y.) 30 39666822

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