Mechanism of MTA1 Protein Overexpression-linked Invasion: MTA1 REGULATION OF HYALURONAN-MEDIATED MOTILITY RECEPTOR (HMMR) EXPRESSION AND FUNCTION

Deivendran Sankaran,Suresh B Pakala,Vasudha S Nair,Divijendra Natha Reddy Sirigiri,Dinesh Cyanam,Ngoc-Han Ha,Da-Qiang Li,T.R Santhoshkumar,M Radhakrishna Pillai,Rakesh Kumar

doi:10.1074/jbc.m111.324632

Abstract

Even though the hyaluronan-mediated motility receptor (HMMR), a cell surface oncogenic protein, is widely up-regulated in human cancers and correlates well with cell motility and invasion, the underlying molecular and nature of its putative upstream regulation remain unknown. Here, we found for the first time that MTA1 (metastatic tumor antigen 1), a master chromatin modifier, regulates the expression of HMMR and, consequently, its function in breast cancer cell motility and invasiveness. We recognized a positive correlation between the levels of MTA1 and HMMR in human cancer. Furthermore, MTA1 is required for optimal expression of HMMR. The underlying mechanism includes interaction of the MTA1·RNA polymerase II·c-Jun coactivator complex with the HMMR promoter to stimulates its transcription. Accordingly, selective siRNA-mediated knockdown of HMMR in breast cancer cells substantially reduces the invasion and migration of cells. These findings reveal a regulatory role for MTA1 as an upstream coactivator of HMMR expression and resulting biological phenotypes.

Highlights

MTA1 is overexpressed in advanced human cancer, its role in cancer invasion and migration needs to be elucidated
We found that the noted correlation between the levels of MTA1 and hyaluronan-mediated motility receptor (HMMR) was not limited to breast cancer, as we noticed a strong correlation between the levels of MTA1 and HMMR mRNAs and proteins in prostate cancer cell lines (Fig. 2A)
MTA1 Regulates HMMR Expression—Because of the existence of a strong correlation between the expression levels of MTA1 and HMMR, we investigated the contribution of MTA1 to the regulation of HMMR

Summary

Background

MTA1 is overexpressed in advanced human cancer, its role in cancer invasion and migration needs to be elucidated. Results: MTA1 transcriptionally stimulates expression of the hyaluronan-mediated motility receptor (HMMR) and regulates cancer invasion and migratory function. We found for the first time that MTA1 (metastatic tumor antigen 1), a master chromatin modifier, regulates the expression of HMMR and, its function in breast cancer cell motility and invasiveness. Selective siRNA-mediated knockdown of HMMR in breast cancer cells substantially reduces the invasion and migration of cells These findings reveal a regulatory role for MTA1 as an upstream coactivator of HMMR expression and resulting biological phenotypes. Both integral components of cancer progression, require an active motile cell phenotype. MTA1 increases the transcriptional activity of hypoxia-inducible factor-1␣ and the expression of VEGF-A, which contribute to the process of metastasis [29, 30]. We discovered that MTA1 is an upstream coactivator of HMMR and is needed for its expression and resulting functions in invasion and migration

EXPERIMENTAL PROCEDURES

RESULTS AND DISCUSSION

ADDITIONS AND CORRECTIONS