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

Abstract

MicroRNA-101, a tumor suppressor microRNA is often down-regulated 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, COX2, POMP, 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 play 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 polo-like kinase PLK1, C-MYC, serine threonine kinase BUB1B and regulates their expression. Additionally, we observed SUB1 down-regulated 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 the prostate cancer and identifies its regulation, and potential downstream therapeutic targets of SUB1 in prostate cancer.

In vitro study of the Polo‐like kinase 1 inhibitor volasertib in non‐small‐cell lung cancer reveals a role for the tumor suppressor p53

“…() and Chakravarthi et al . (). Importantly, in these publications, the TP53 status was not taken into account.…”

Quantitative Proteomics to Identify Nuclear RNA-Binding Proteins of Malat1

“…There are some not yet known interactors in our screen that might be interesting candidates for future functional studies. Among the candidates unique to our study are several proteins described to be involved in different cancer types in humans: for example, NOLC1 in multidrug resistant non-small cell lung cancer (the same cancer MALAT1 has originally been identified) [33], DEK in breast cancer [34] and SUB1 in prostate cancer [35]. Intriguingly, we found two bromodomain containing proteins (BRD2 and BRD3) noted to be relevant in cancer [36] interacting with MALAT1.…”

MiR‐181a/b induce the growth, invasion, and metastasis of neuroblastoma cells through targeting ABI1

“…Recent studies have identified that several miRNAs have oncogenic or tumor suppressing functions in human cancers, contributing to malignant progression and specifically mediating tumor invasion and metastasis . We postulated that alterations in miRNA expression levels might contribute to the characteristic aggressive and metastatic behavior of neuroblastomas.…”

“…Recent studies have identified that several miRNAs have oncogenic or tumor suppressing functions in human cancers, contributing to malignant progression and specifically mediating tumor invasion and metastasis. [31][32][33][34][35] We postulated that alterations in miRNA expression levels might contribute to the characteristic aggressive and metastatic behavior of neuroblastomas. Our results show that miR-181a/b positively regulate in vitro neuroblastoma proliferation, migration and invasion as well as in vivo tumor tumorigenesis and metastasis by modulating GTPase-mediated signaling, including ABI1.…”