Gene rearrangement is reported to be associated to the aggressive phenotype and poor prognosis in prostate cancer. We identified a gene fusion between a transcription repressor (BMI1) and transcriptional factor (COMMD3) in human prostate cancer. We show that COMMD3:BMI1 fusion expression is significantly increased in prostate cancer disease in an order: normal tissue < primary < metastatic tumors (Mets). Although elevated TMPRSS-ERG/ETV fusion is reported in prostate cancer, we identified a subtype of Mets exhibiting low TMPRSS:ETV and high COMMD3:BMI1. We delineated the mechanism and function of COMMD3 and COMMD3: BMI1 in prostate cancer. We show that COMMD3 level is elevated in prostate cancer cell models, PDX models (adeno-carcinoma, NECaP), and Mets. The analysis of TCGA/NIH/ GEO clinical data showed a positive correlation between increased COMMD3 expression to the disease recurrence and poor survival in prostate cancer. We show that COMMD3 drives proliferation of normal cells and promotes migration/ invasiveness of neoplastic cells. We show that COMMD3:BMI1 and COMMD3 regulate C-MYC transcription and C-MYC downstream pathway. The ChIP analysis showed that COMMD3 protein is recruited at the promoter of C-MYC gene. On the basis of these data, we investigated the relevance of COMMD3:BMI1 and COMMD3 as therapeutic targets using in vitro and xenograft mouse models. We show that siRNA-mediated targeting of COMMD3:BMI1 and COMMD3 significantly decreases (i) C-MYC expression in BRD/BET inhibitor–resistant cells, (ii) proliferation/invasion in vitro, and (iii) growth of prostate cancer cell tumors in mice. The IHC analysis of tumors confirmed the targeting of COMMD3-regulated molecular pathway under in vivo conditions. We conclude that COMMD3:BMI1 and COMMD3 are potential progression biomarkers and therapeutic targets of metastatic prostate cancer.
Bibliographical noteFunding Information:
The author (Mohammad Saleem) is supported by the US PHS grants (CA193739, CA184685, CA184685-02S1), UoM Dean's commitment startup (UCMED09293), and Masonic cancer center research support (UMF0011369). B.R. Konety is supported by US PHS grant (U54MD008620-06) and DOD grant (W81XWH-17-1-0462). We thank the Prostate Cancer Biorepository network (PCBN) research team (Dr. Bruce J. Trock, Kathy Willey Johns Hopkins University, Baltimore, MD) for providing race-based matched RNA/DNA of patients. The PCBN tissue procurement is supported by the Department of Defense Prostate Cancer Research Programs (W81XWH-14-2-0182). The University of Washington Prostate Cancer Donor Rapid Autopsy Program is supported by funding from the Department of the Pacific Northwest Prostate Cancer SPORE (P50CA97186) and the Institute for Prostate Cancer Research. We thank the patients and their families, Celestia Higano, Pete Nelson, Elahe Mostaghel, Bruce Montgomery, Lawrence True, Paul Lange, Robert Vessella and the rapid autopsy teams for their contributions to the University of Washington Rapid Autopsy Program. We also acknowledge the support of NCI-sponsored Cooperative Tissue Network (CHTN) and the BioNet-biorepository of the Masonic Cancer Center, University of Minnesota for providing tumor tissues.
© 2019 American Association for Cancer Research.