P53 Target Gene SMAR1 Is Dysregulated in Breast Cancer: Its Role in Cancer Cell Migration and Invasion

Kamini Singh,Gopal Pande,Devraj Mogare,Ramprasad Obula Giridharagopalan,Samit Chattopadhyay,Rajinikanth Gogiraju,Neil Hotchin

doi:10.1371/journal.pone.0000660

Abstract

Tumor suppressor SMAR1 interacts and stabilizes p53 through phosphorylation at its serine-15 residue. We show that SMAR1 transcription is regulated by p53 through its response element present in the SMAR1 promoter. Upon Doxorubicin induced DNA damage, acetylated p53 is recruited on SMAR1 promoter that allows activation of its transcription. Once SMAR1 is induced, cell cycle arrest is observed that is correlated to increased phospho-ser-15-p53 and decreased p53 acetylation. Further we demonstrate that SMAR1 expression is drastically reduced during advancement of human breast cancer. This was correlated with defective p53 expression in breast cancer where acetylated p53 is sequestered into the heterochromatin region and become inaccessible to activate SMAR1 promoter. In a recent report we have shown that SMAR1 represses Cyclin D1 transcription through recruitment of HDAC1 dependent repressor complex at the MAR site of Cyclin D1 promoter. Here we show that downmodulation of SMAR1 in high grade breast carcinoma is correlated with upregulated Cyclin D1 expression. We also established that SMAR1 inhibits tumor cell migration and metastases through inhibition of TGFβ signaling and its downstream target genes including cutl1 and various focal adhesion molecules. Thus, we report that SMAR1 plays a central role in coordinating p53 and TGFβ pathways in human breast cancer.

Highlights

Nuclear matrix and matrix binding proteins maintain chromatin architecture that is altered in cancer [1]
These results suggested that SMAR1 is downmodulated during breast cancer progression, which might be due to defective p53 function and as a consequence, Cyclin D1 expression is upregulated in the absence of its negative regulator SMAR1
Smar1, located at 16q24.3 is a ubiquitously expressed MARBP. It is downregulated in many transformed cell lines including breast carcinoma cell lines MCF7, Hbl-100, MDA-MB-231, MDA-MB-468 etc. [36,38]. Based on these findings we investigated the status of SMAR1 expression in human breast cancer patient samples

Summary

Introduction

Nuclear matrix and matrix binding proteins maintain chromatin architecture that is altered in cancer [1]. MAR (Matrix Attachment Region) binding proteins (MARBPs) like p53, Ku, PARP, SATB1, Cux/CDP are involved in regulation of various physiological processes that include cell cycle progression, DNA damage-repair, apoptosis etc. DNA damage and other stress induce p53 mediated cell cycle arrest, apoptosis and cellular senescence through post-translational modification of p53 like phosphorylation, acetylation, sumoylation etc. Among all Cyclins, Cyclin D1 expression is one of the hallmarks of breast cancer progression and is considered as a positive diagnostic marker [11,12] Various growth factors such as IGF I, IGF II, TGF-b, retinoic acid etc. Apart from these growth factors, oncogenic signals mediated by Ras, Src, Stats and Erb that are involved in cellular transformation activate Cyclin D1 [17,13,18,19]

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