ST7

ST7 (also classified as LRP12) is a cytoplasmic transmembrane protein of the LDLR superfamily that functions as a tumor suppressor by remodeling the extracellular matrix and restraining epithelial-to-mesenchymal transition. Re-expression of ST7 in prostate and breast cancer cells suppresses tumorigenicity in vivo and anchorage-independent growth, predominantly through transcriptional changes in extracellular matrix genes including SPARC, IGFBP5, and matrix metalloproteinases (PMID:11279520, PMID:16474848). Mechanistically, ST7 binds the transcription/translation regulator YBX1 and prevents its nuclear translocation, thereby suppressing MMP14 transcription and EMT-driven metastasis (PMID:42025890). ST7 expression is epigenetically repressed by PRMT5-mediated H3R8 methylation at its promoter (PMID:15485929), and ST7 protein is targeted for proteasomal degradation by both the CRL4^DCAF4 complex (transcriptionally activated by c-Myc) and the E3 ligase MIB1, linking oncogenic signaling to ST7 inactivation (PMID:30945288, PMID:33793053).

1. 2001 High

   Whether ST7 had tumor-suppressive function was unknown; introduction of ST7 cDNA into PC3 prostate cancer cells abolished xenograft tumorigenicity without affecting proliferation in vitro, establishing ST7 as a bona fide tumor suppressor acting in vivo.

   Evidence ST7 cDNA gain-of-function in PC3 cells followed by nude mouse xenograft assay

   PMID:11279520

   Open questions at the time

   • Mechanism of tumor suppression uncharacterized
   • No downstream targets identified
   • Relevance beyond prostate cancer untested
2. 2003 Medium

   The molecular identity of ST7 as a signaling-competent receptor and its proximal cytoplasmic partners were unknown; classification of ST7 as an LDLR superfamily member (LRP12) and identification of RACK1, MIBP, and SARA as cytoplasmic domain interactors suggested roles in signal transduction and endocytosis.

   Evidence Proteomic domain analysis and yeast two-hybrid screen of the ST7 cytoplasmic domain

   PMID:12809483

   Open questions at the time

   • Interactions identified only by yeast two-hybrid without reciprocal co-IP validation
   • Functional relevance of RACK1/MIBP/SARA binding to tumor suppression not tested
   • Ligand for the extracellular domain unknown
3. 2004 High

   How ST7 expression is silenced in cancer was unclear; PRMT5, in complex with SWI/SNF chromatin remodelers, was shown to methylate H3R8 at the ST7 promoter, causing H3K9 deacetylation and transcriptional repression, establishing an epigenetic mechanism for ST7 silencing.

   Evidence PRMT5 antisense knockdown, ChIP at the ST7 promoter, in vitro histone methylation assay, overexpression in NIH 3T3 cells

   PMID:15485929

   Open questions at the time

   • Whether H3R8 methylation is the sole epigenetic mechanism silencing ST7 is untested
   • Cancer-type specificity of PRMT5-mediated repression not defined
   • Contributions of BRG1 vs. hBRM sub-complexes not dissected
4. 2006 Medium

   The downstream effector program of ST7 tumor suppression was unknown; expression profiling upon ST7 re-expression revealed predominant changes in extracellular matrix genes (SPARC, IGFBP5, MMPs), indicating ST7 suppresses tumors by remodeling the microenvironment.

   Evidence Xenograft assay in SCID mice, soft-agar colony formation in MDA-MB-231 cells, microarray expression profiling

   PMID:16474848

   Open questions at the time

   • Direct versus indirect transcriptional regulation not resolved
   • Whether ECM remodeling is necessary or sufficient for tumor suppression untested
   • Upstream signaling from ST7 to gene expression changes uncharacterized
5. 2010 Medium

   ST7 subcellular localization and relationship to cell cycle were undefined; fluorescence imaging placed ST7 exclusively in the cytoplasm, and synchronization experiments showed ST7 is upregulated during cell cycle arrest and downregulated upon re-entry into division.

   Evidence Fluorescence microscopy of tagged ST7 fusion proteins; cell cycle synchronization with gene expression analysis

   PMID:20238225

   Open questions at the time

   • Causal role of ST7 in cell cycle arrest versus correlation not distinguished
   • Whether cytoplasmic retention is regulated under specific stimuli not tested
   • Connection between cell cycle expression pattern and tumor suppression unclear
6. 2019 High

   How ST7 protein levels are regulated post-translationally was unknown; the CRL4^DCAF4 E3 ubiquitin ligase complex was shown to ubiquitinate and target ST7 for proteasomal degradation, with c-Myc transcriptionally driving CUL4A/CUL4B expression to accelerate ST7 turnover and promote tumorigenesis.

   Evidence In vitro and in vivo ubiquitination assays, reciprocal co-IP, ChIP for c-Myc at CUL4 promoters, knockdown/rescue with colony formation and xenograft assays

   PMID:30945288

   Open questions at the time

   • Specific degron motif on ST7 recognized by DCAF4 not mapped
   • Relative contributions of CUL4A versus CUL4B not resolved
   • Whether other substrates of CRL4^DCAF4 contribute to the tumorigenic phenotype not excluded
7. 2021 Medium

   Whether additional E3 ligases regulate ST7 degradation and what effectors lie downstream of ST7 loss in pancreatic cancer were unknown; MIB1 was identified as a second E3 ligase targeting ST7 for degradation, and IQGAP1 was defined as a downstream mediator of ST7-dependent tumor suppression.

   Evidence MIB1 overexpression/knockdown, proteasomal degradation assays, in vitro and in vivo proliferation/invasion assays in pancreatic cancer cells

   PMID:33793053

   Open questions at the time

   • Ubiquitination sites on ST7 targeted by MIB1 not mapped
   • Mechanism by which ST7 regulates IQGAP1 levels not defined
   • Whether MIB1 and CRL4^DCAF4 act redundantly or in distinct contexts not tested
8. 2026 Medium

   The direct protein partner through which ST7 suppresses EMT and metastasis was unknown; ST7 was shown to bind YBX1 and block its nuclear translocation, thereby reducing MMP14 transcription and inhibiting EMT-driven metastatic progression in NSCLC.

   Evidence Co-IP of ST7–YBX1, nuclear translocation assay, MMP14 expression analysis, in vitro EMT assays, tail-vein lung metastasis model

   PMID:42025890

   Open questions at the time

   • Structural basis of ST7–YBX1 interaction not determined
   • Whether YBX1 sequestration accounts for all ST7 tumor-suppressive activity not tested
   • Relevance of the ST7–YBX1–MMP14 axis outside NSCLC not established

• The ligand for the extracellular LDLR-related domain of ST7 and how extracellular engagement connects to cytoplasmic tumor-suppressive signaling remain unknown.
• No extracellular ligand identified
• No structural model of full-length ST7
• Integration of RACK1/SARA interactions with YBX1 binding and ECM gene regulation not resolved