ST7

ST7 (LRP12) is a tumor suppressor on chromosome 7q31 whose re-expression abrogates in vivo tumorigenicity of prostate and breast cancer cells without altering in vitro proliferation (PMID:11279520, PMID:16474848). It is a cytoplasmic transmembrane member of the LDLR superfamily; its cytoplasmic domain carries endocytosis and signaling motifs and interacts with RACK1, MIBP, and SARA in yeast two-hybrid assays (PMID:12809483), and the protein localizes to the cytoplasm rather than the nucleus across multiple cancer cell lines (PMID:20238225). ST7 exerts tumor suppression largely by reshaping the tumor microenvironment, predominantly inducing changes in extracellular matrix remodeling genes including SPARC, IGFBP5, and matrix metalloproteinases (PMID:16474848). Mechanistically, ST7 binds YBX1 and blocks its nuclear translocation, repressing MMP14 expression and inhibiting EMT and metastasis (PMID:42025890), and its loss upregulates IQGAP1 to drive proliferation and invasion (PMID:33793053). ST7 expression is controlled at two levels: transcriptionally, PRMT5 associated with hSWI/SNF (BRG1/hBRM) chromatin-remodeling complexes methylates histone H3 at arginine 8 at the ST7 promoter, triggering H3K9 deacetylation and repression (PMID:15485929); and post-translationally, the CRL4DCAF4 ligase complex (driven by c-Myc-induced CUL4A/CUL4B) and the MIB1 E3 ligase target ST7 for proteasomal degradation (PMID:30945288, PMID:33793053).

1. 2001 Medium

   Establishing whether the 7q31 candidate ST7 had genuine tumor-suppressor activity required functional testing; re-expression demonstrated it suppresses tumorigenicity in vivo without affecting cell-intrinsic proliferation, defining a microenvironment-dependent suppressor.

   Evidence ST7 cDNA re-expression in PC3 prostate cancer cells with subcutaneous tumor formation assay in nude mice

   PMID:11279520

   Open questions at the time

   • Molecular mechanism of suppression undefined
   • No identified binding partners or pathway
   • Single tumor model
2. 2003 Low

   The molecular identity and interaction potential of ST7 were unknown; domain analysis placed it in the LDLR superfamily (LRP12) with a cytoplasmic domain bearing endocytosis and signaling motifs that bind RACK1, MIBP, and SARA, implicating it in endocytosis and signal transduction.

   Evidence Bioinformatic domain analysis and yeast two-hybrid screening

   PMID:12809483

   Open questions at the time

   • Yeast two-hybrid interactions not validated in cells
   • Functional consequence of RACK1/MIBP/SARA binding untested
   • No link to tumor-suppressor phenotype
3. 2004 High

   How ST7 is silenced in cancer was unresolved; PRMT5 within hSWI/SNF complexes was shown to methylate H3R8 at the ST7 promoter and trigger H3K9 deacetylation, defining an epigenetic repression mechanism.

   Evidence PRMT5 antisense knockdown, microarray, ChIP at the ST7 promoter, and in vitro histone methylation with recombinant PRMT5

   PMID:15485929

   Open questions at the time

   • Upstream signals controlling PRMT5 recruitment to ST7 promoter unknown
   • Whether silencing is reversible in vivo not addressed
4. 2006 Medium

   The downstream effector program of ST7 suppression was unknown; expression profiling tied suppression to extracellular matrix remodeling, indicating ST7 acts through modification of the tumor microenvironment.

   Evidence ST7 re-expression with SCID xenograft and soft-agar assays plus expression profiling identifying SPARC, IGFBP5, and MMP changes

   PMID:16474848

   Open questions at the time

   • Direct vs indirect regulation of ECM genes unresolved
   • No molecular partner linking ST7 to transcriptional output
5. 2010 Medium

   The subcellular site of ST7 action and its cell-cycle behavior were uncharacterized; live-cell imaging confirmed cytoplasmic localization with no nuclear translocation, and synchronization linked ST7 (with SERPINE1) to cell-cycle arrest.

   Evidence GFP/YFP/V5-tagged ST7 fluorescence microscopy with cell-cycle synchronization and RT-PCR

   PMID:20238225

   Open questions at the time

   • Mechanism coupling ST7 to cell-cycle arrest unknown
   • Functional significance of SERPINE1 co-regulation unclear
6. 2019 High

   Post-translational control of ST7 abundance was undefined; the CRL4DCAF4 complex was shown to ubiquitinate ST7 for degradation, with c-Myc activating CUL4A/CUL4B to lower ST7 in colitis-associated cancer.

   Evidence In vitro and in vivo ubiquitination assays, co-IP, promoter ChIP, knockdown/overexpression, and xenograft model

   PMID:30945288

   Open questions at the time

   • Degron on ST7 recognized by DCAF4 not mapped
   • Generality beyond colitis-associated cancer untested
7. 2021 Medium

   A second degradation route and a proliferation/invasion effector were unknown; MIB1 was shown to degrade ST7, and ST7 loss derepressed IQGAP1, defining a MIB1/ST7/IQGAP1 axis in pancreatic cancer.

   Evidence Co-IP, ubiquitination assay, knockdown/overexpression, proliferation/invasion assays, and xenograft model

   PMID:33793053

   Open questions at the time

   • Mechanism of ST7-mediated IQGAP1 suppression not resolved
   • Relative contribution of MIB1 vs CRL4DCAF4 across tissues unknown
8. 2026 Medium

   How cytoplasmic ST7 controls a transcriptional metastatic program was unresolved; ST7 was shown to bind YBX1 and block its nuclear entry, repressing MMP14 and EMT, providing a direct molecular link between ST7 and ECM/EMT output.

   Evidence Co-IP of ST7–YBX1, nuclear translocation assays, EMT assays, and tail-vein lung metastasis mouse model

   PMID:42025890

   Open questions at the time

   • Structural basis of ST7–YBX1 binding unknown
   • Whether YBX1 sequestration explains the broader ECM program of [#3] untested

• How ST7's LDLR-superfamily receptor architecture and putative endocytic/signaling partners (RACK1, MIBP, SARA) integrate with its cytoplasmic YBX1/IQGAP1 effector functions remains unresolved.
• No unifying mechanism linking receptor domain to tumor-suppressor signaling
• Endocytic role suggested by domain analysis never functionally tested