Sox7 negatively regulates prostate‐specific membrane antigen (PSMA) expression through PSMA‐enhancer

Abstract

Background PSMA expression in the prostate epithelium is controlled by a cis‐element, PSMA enhancer (PSME). PSME contains multiple binding sites for Sox proteins, and in this study, we identified Sox7 protein as a negative regulator of PSMA expression through its interaction with PSME. Methods The statistical correlation between Sox7 and PSMA mRNA expression was evaluated using five prostate cancer studies from cBioportal. In vitro and in vivo interaction between Sox7 and PSME was evaluated by chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and luciferase reporter assay. Synthetic oligonucleotides were generated to define the sites in PSME that interact with Sox7 protein. Sox7 mutants were generated to identify the region of this protein required to regulate PSMA expression. Sox7 was also stably expressed in LNCaP/C4‐2 and 22Rv1 cells to validate the regulation of PSMA expression by Sox7 in vivo. Results Sox7 mRNA expression negatively correlated with PSMA/FOLH1 and PSMAL/FOLH1B mRNA expression in Broad/Cornell, TCGA and MSKCC studies, but not in two studies containing only metastatic prostate tumors. PC‐3 cells mostly expressed the 48.5 KDa isoform 2 of Sox7, and the depletion of this isoform did not restore PSMA expression. Ectopic expression of canonical, wild‐type Sox7 in C4‐2 and 22Rv1 cells suppressed PSMA protein expression. ChIP assay revealed that canonical Sox7 protein preferentially interacts with PSME in vivo, and EMSA identified the SOX box sites #2 and #4 in PSME as required for its interaction. Sox7 was capable of directly binding to PSME and suppressed PSME‐mediated transcription. The NLS regions of Sox7, but not its β‐catenin interacting motif, are essential for this suppressing activity. Furthermore, restoration of wild‐type Sox7 expression but not Sox7‐NLS mutant in Sox7‐null prostate cancer cell lines suppressed PSMA expression. Conclusions The inactivation of canonical Sox7 is responsible for the upregulated expression of PSMA in non‐metastatic prostate cancer.

Regulation of DEAH-box RNA helicases by G-patch proteins

“…It has not been addressed whether isoform 2 of SOX7 is imported into the nucleus or whether it has a cytoplasmic function. However, in a prostate cancer cell line, which mainly expresses isoform 2, transcriptional activation of enhancers targeted by SOX7 was not dependent on isoform 2 and could only be rescued by ectopic expression of isoform 1, suggesting that the G-patch-containing SOX7 might have additional roles in cells where it is expressed (Peng et al 2019).…”

“…It inhibits Wnt signalling by directly binding β-catenin via its central domain and blocking β-cateninmediated transcription activation (Takash et al 2001;Zorn et al 1999). Interestingly, only SOX7 isoform 2 encodes a canonical G-patch motif, which replaces the N-terminal nuclear localization signal of isoform 1 (Peng et al 2019). It has not been addressed whether isoform 2 of SOX7 is imported into the nucleus or whether it has a cytoplasmic function.…”

miR-146a Inhibited Pancreatic Cancer Cell Proliferation by Targeting SOX7

“…A previous study demonstrated that the expression of SOX7 mRNA was frequently downregulated in many human cancer cell lines and tumor tissues [ 12 ]. Some members of the SOX family are negative regulators of the WNT-b-catenin-TCF signaling pathway [ 13 ].…”

“…SOX7, a member of subgroup F along with SOX17 and SOX18, has been reported to regulate hematopoiesis and cardiogenesis originally. Furthermore, accompanied with the increasing evidence, SOX7 in particular has also been revealed to be a tumor suppressor in a number of human cancers [ 12 ]. For example, its downregulation was observed in tumors from the ovary, stomach, and lungs [ 14 ].…”

Secreted Phosphoprotein 1 (SPP1) Promotes Angiogenesis of Glioblastoma Through Up-regulating PSMA Expression Via Transcription Factor HIF-1α

“…It was merely reported that PSMA expression was regulated by a cis-element, the PSMA enhancer (PSME), in prostate epithelium [32]. Moreover, PSME could be negatively regulated by Sox7 protein [33]. As the above mechanism was not exclusive to tumors, it could not apply to our study, which unraveled the speci c mechanism of GBMinduced PSMA upregulation.…”