Overexpression of PCDH7 and SET Leads to Aberrant ERK and AKT Signaling and Promotes Prostate Cancer Progression

Abstract

IntroductionPI3K/AKT and RAF/MEK/ERK signaling pathways play an important role in cell survival and treatment resistance to facilitate prostate cancer (PCa) progression to castration resistant prostate cancer (CRPC). Most of PCa deaths are a result of distant metastasis. PCDH7, a cadherin superfamily transmembrane protein, is involved in cell‐cell recognition and adhesion. Recent reports suggest overexpression of PCDH7 promotes metastasis in lung and breast cancer and PCDH7 was shown to interact with SET in lung cancer. Overexpression of SET promoted cell proliferation, survival, drug resistance, invasion and metastasis in different cancers. We evaluated expression and function of PCDH7 and SET in PCa.Materials and MethodsPCDH7 and SET expression in clinical samples was extracted from publically available data sets (CRPC/NEPC‐Trento et al 2016; TCGA, Cell 2015; adenocarcinoma‐MSKCC, Cancer Cell 2010 using cBioPortal and UALCAN). PCa cells‐LNCaP, C4‐2B, DU145, PC3, 22Rv1 and RWPE1 were used in this study. Protein expression was measured by Western blotting in cell lines and immunohistochemistry in FFPE TRAMP and human prostate tissue sections. Gene expression was monitored by quantitative real time PCR. Gene knock down was performed by shRNA using lentiviral expression. Colony formation was assessed by staining with 0.4% crystal violet after 3 weeks of cell seeding. Co‐IP studies were performed to check interactions of PCDH7 with SET.ResultsOur results show that PCDH7 mRNA is overexpressed in 43% patients in CRPC as compared to 4% of patients in TCGA data set. SET was amplified in 23% of NEPC patients (Trento, 2016), mRNA upregulation in more than 5% adenocarcinoma patients (TCGA, 2015 and MSKCC, 2010). TCGA dataset showed that SET expression is high in tumor samples of adenocarcinoma patients as compared to normal prostate and increase in SET expression was observed with increase in Gleason score (UALCAN). PCDH7 mRNA and protein is overexpressed in CRPC (C4‐2B, 22Rv1, DU145 and PC3) cells as compared to castrations sensitive (LNCaP) cells and normal prostate (RWPE1) cells. We also observed increased expression of PCDH7 in prostate tissues of TRAMP mice during PCa progression. Increase in PCDH7 expression was observed with increase in Gleason score in human PCa tissues as compared to normal tissues. We observed that knocking down PCDH7 and SET decreased colony formation, and PCDH7 knock down reduced ERK and AKT activities. Co‐IP studies revealed that PCDH7 interacts with SET. Collectively, these data suggest PCDH7 and SET are overexpressed in PCa and promote PCa progression.ConclusionOur results, for the first time, show overexpression of PCDH7 and SET in PCa, as such PCDH7 may be an attractive target for therapeutic intervention in subsets of CRPC patients.Support or Funding InformationCarroll W. Feist endowed Chair funds (Koul H), FWCC‐HRM funds (Koul H‐LSUHSC‐Shreveport). We acknowledge core facility at LSUHSC‐Shreveport for help in performing cell migration and cell invasion studies, Dr. Prakash Srinivasan Timiri Shanmugam for maintaining TRAMP tissues in the lab.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.