COMMD3:BMI1 Fusion and COMMD3 Protein Regulate C-MYC Transcription: Novel Therapeutic Target for Metastatic Prostate Cancer

Abstract

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 (adenocarcinoma, 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 siRNAmediated targeting of COMMD3:BMI1 and COMMD3 significantly decreases (i) C-MYC expression in BRD/BET inhibitorresistant 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.

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

“…The role of DNAJC1, COMMD3 and SPAG6 in MLLT10 r acute leukemia is yet to be investigated, but both COMMD3 and SPAG6 have implicated roles in other malignancies. COMMD3 levels are elevated in prostate cancer, and have been demonstrated to upregulate C‐MYC expression, promoting proliferation in prostate cancer models 74 . SPAG6 is a member of the cancer‐testis antigen family primarily involved in regulation of the microtubule system, with secondary roles associated with inhibition of the Akt and p53 pathways 75 .…”

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

“…In the light cyan module, Extl2 (Exostosin-like 2) codes for a glycosyltransferase from the exostosin family that modifies the heparin sulfate structure and is involved with breast cancer cell adhesion and invasion [ 16 ]. In addition, the hub gene Commd3 (COMM domain-containing 3) was shown to regulate c-myc transcription and prostate tumor growth in mice [ 17 ].…”

“…In the light cyan module, Extl2 (Exostosin-like 2) codes for a glycosyltransferase from the exostosin family that modifies the heparin sulfate structure and is involved with breast cancer cell adhesion and invasion [16]. In addition, the hub gene Commd3 (COMM The functions, pathways, and histone marks were considered to be significantly enriched if their adjusted p values were less than 0.05 domain-containing 3) was shown to regulate c-myc transcription and prostate tumor growth in mice [17]. The red, salmon, turquoise, and magenta modules were positively correlated with EMT (Fig.…”

Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer

“…Fusion genes are a class of oncogenes that have been found in many cancer types including PCa and caused by genomic rearrangements [36]. Gene fusion between a transcription repressor (BMI1) and a transcriptional factor (COMMD3) has been recently identified in PCa, which triggers disease recurrence and poor survival [37]. It was reported that targeting the COMMD3:BMI1 fusion gene with siRNA leads to reduced c-MYC expression and decreased tumor cell proliferation both in vitro and in metastatic tumors in a xenograft mouse model of PCa [37].…”