Functional interplay between YY1 and CARM1 promotes oral carcinogenesis.

Amit K Behera,Akshay Bhat,Madavan Vasudevan,Kodaganur S Gopinath,Muthu K Shanmugam,Aditya Bhattacharya,Tapas K Kundu,Azeem Mohiyuddin,Anupam Chatterjee,Manoj Kumar,Vinay J Rao,Gautam Sethi

doi:10.18632/oncotarget.26984

Abstract

Coactivator associated arginine methyltransferase 1 (CARM1) has been functionally implicated in maintenance of pluripotency, cellular differentiation and tumorigenesis; where it plays regulatory roles by virtue of its ability to coactivate transcription as well as to modulate protein function as an arginine methyltransferase. Previous studies establish an oncogenic function of CARM1 in the context of colorectal and breast cancer, which correlate to its overexpressed condition. However, the mechanism behind its deregulated expression in the context of cancer has not been addressed before. In the present study we uncover an oncogenic function of CARM1 in the context of oral cancer, where it was found to be overexpressed. We also identify YY1 to be a positive regulator of CARM1 gene promoter, where silencing of YY1 in oral cancer cell line could lead to reduction in expression of CARM1. In this context, YY1 showed concomitant overexpression in oral cancer patient samples compared to adjacent normal tissue. Cell line based experiments as well as xenograft study revealed pro-neoplastic functions of YY1 in oral cancer. Transcriptomics analysis as well as qRT-PCR validation clearly indicated pro-proliferative, pro-angiogenic and pro-metastatic role of YY1 in oral cancer. We also show that YY1 is a substrate of CARM1 mediated arginine methylation, where the latter could coactivate YY1 mediated reporter gene activation in vivo. Taken together, CARM1 and YY1 were found to regulate each other in a positive feedback loop to facilitate oral cancer progression.

Highlights

Ying Yang 1 (YY1) regulates expression of a wide range of genes involved in multitude of cellular processes such as proliferation, differentiation and apoptosis [1]
We identify YY1 to be a positive regulator of Coactivator associated arginine methyltransferase 1 (CARM1) gene promoter, where silencing of YY1 in oral cancer cell line could lead to reduction in expression of CARM1
As our results clearly suggest that YY1 positively regulates CARM1 promoter and CARM1 is highly overexpressed in oral cancer patient samples, we wanted to find out whether CARM1 overexpression is caused by upregulation of YY1 in the context of oral cancer

Summary

INTRODUCTION

YY1 regulates expression of a wide range of genes involved in multitude of cellular processes such as proliferation, differentiation and apoptosis [1]. In certain forms of cancer, YY1 expression shows unfavorable association with tumorigenesis [5] Existence of such conflicting scientific evidences indicates a very complex network of genes regulated by YY1, where fine balance among them in different conditions can dictate the outcome [6, 7]. Several studies suggest both oncogenic and tumor suppressor function of YY1 in breast cancer progression. Keeping in mind the need of the hour, we put our effort in the present study to elucidate the molecular function of CARM1, a prospective oncogenic candidate and a probable therapeutic target in the context of oral cancer. We uncover interplay between YY1 and CARM1 that promotes oral carcinogenesis

RESULTS

DISCUSSION

MATERIALS AND METHODS