MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer.

B V S K Chakravarthi,M T Goswami,S S Pathi,N Palanisamy,S Daignault,X Jing,S Agarwal,S Varambally,M Cieślik,J Siddiqui,A M Chinnaiyan,D S Chandrashekar,A D Robinson,S L Carskadon,L P Kunju

doi:10.1038/onc.2016.164

Abstract

MicroRNA-101, a tumor suppressor microRNA (miR), is often downregulated in cancer and is known to target multiple oncogenes. Some of the genes that are negatively regulated by miR-101 expression include histone methyltransferase EZH2 (enhancer of zeste homolog 2), COX2 (cyclooxygenase-2), POMP (proteasome maturation protein), CERS6, STMN1, MCL-1 and ROCK2, among others. In the present study, we show that miR-101 targets transcriptional coactivator SUB1 homolog (Saccharomyces cerevisiae)/PC4 (positive cofactor 4) and regulates its expression. SUB1 is known to have diverse role in vital cell processes such as DNA replication, repair and heterochromatinization. SUB1 is known to modulate transcription and acts as a mediator between the upstream activators and general transcription machinery. Expression profiling in several cancers revealed SUB1 overexpression, suggesting a potential role in tumorigenesis. However, detailed regulation and function of SUB1 has not been elucidated. In this study, we show elevated expression of SUB1 in aggressive prostate cancer. Knockdown of SUB1 in prostate cancer cells resulted in reduced cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Gene expression analyses coupled with chromatin immunoprecipitation revealed that SUB1 binds to the promoter regions of several oncogenes such as PLK1 (Polo-like kinase 1), C-MYC, serine-threonine kinase BUB1B and regulates their expression. Additionally, we observed SUB1 downregulated CDKN1B expression. PLK1 knockdown or use of PLK1 inhibitor can mitigate oncogenic function of SUB1 in benign prostate cancer cells. Thus, our study suggests that miR-101 loss results in increased SUB1 expression and subsequent activation of known oncogenes driving prostate cancer progression and metastasis. This study therefore demonstrates functional role of SUB1 in prostate cancer, and identifies its regulation and potential downstream therapeutic targets of SUB1 in prostate cancer.

Highlights

Prostate cancer is the most common malignancy and the second most common cause of cancer death among men in the United States.[1]
MiR-101 is known to have tumor suppressor function by targeting several oncogenes including enhancer of zeste homolog 2 (EZH2),11 proteasome assembly factor POMP,[13] COX2,12 and others, we sought to determine its role in SUB1 regulation
We show that miR-101 regulates SUB1 expression and SUB1 has a role in prostate cancer growth

Summary

Introduction

Prostate cancer is the most common malignancy and the second most common cause of cancer death among men in the United States.[1]. Further investigations are needed to understand the mechanisms of dysregulation and role in tumorigenesis of many of the dysregulated genes that are implicated in cancer. These studies will enhance the understanding of the disease process and help in developing new therapies. Our previous studies showed that genomic loci encoding miR-101 were deleted in aggressive prostate cancer leading to reduced miR-101 expression, resulting in overexpression of histone methyltransferase enhancer of zeste homolog 2 (EZH2).[11] Apart from regulating EZH2, it has been shown that miR-101 can target other critical genes such as COX2

Methods

Results

Conclusion