Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo.

Ankana Tiwari,Shivananda Swamy,Kodaganur S Gopinath,Arun Kumar

doi:10.1038/srep17621

Abstract

The ESRRA gene encodes a transcription factor and regulates several genes, such as WNT11 and OPN, involved in tumorigenesis. It is upregulated in several cancers, including OSCC. We have previously shown that the tumor suppressor miR-125a targets ESRRA, and its downregulation causes upregulation of ESRRA in OSCC. Upregulation of ESRRA in the absence of downregulation of miR-125a in a subset of OSCC samples suggests the involvement of an alternative mechanism. Using TaqMan® copy number assay, here we report for the first time that the genomic amplification of ESRRA causes its upregulation in a subset of OSCC samples. Ectopic overexpression of ESRRA led to accelerated cell proliferation, anchorage-independent cell growth and invasion, and inhibited apoptosis. Whereas, knockdown of ESRRA expression by siRNA led to reduced cell proliferation, anchorage-independent cell growth and invasion, and accelerated apoptosis. Furthermore, the delivery of a synthetic biostable ESRRA siRNA to OSCC cells resulted in regression of xenografts in nude mice. Thus, the genomic amplification of ESRRA is another novel mechanism for its upregulation in OSCC. Based on our in vitro and in vivo experiments, we suggest that targeting ESRRA by siRNA could be a novel therapeutic strategy for OSCC and other cancers.

Highlights

ESRRA causes its upregulation in a subset of Oral squamous cell carcinoma (OSCC) samples
We have recently reported that the downregulation of tumor suppressor miR125a is one of the major mechanisms for upregulation of ESRRA in a subset of OSCC samples[11]
® Using TaqMan copy number assay, here we show for the first time that the genomic amplification of ESRRA is another novel mechanism for its upregulation in OSCC

Summary

Introduction

ESRRA causes its upregulation in a subset of OSCC samples. Ectopic overexpression of ESRRA led to accelerated cell proliferation, anchorage-independent cell growth and invasion, and inhibited apoptosis. Knockdown of ESRRA expression by siRNA led to reduced cell proliferation, anchorage-independent cell growth and invasion, and accelerated apoptosis. Based on our in vitro and in vivo experiments, we suggest that targeting ESRRA by siRNA could be a novel therapeutic strategy for OSCC and other cancers. ESRRA harbors a DNA binding domain (amino acids 73–168), which is composed of two C4-type zinc fingers, a ligand binding domain (amino acids 197–420) and a monopartite nuclear localization signal (amino acids 71 LSSLPKRLCLV 81) It is expressed at high levels in tissues with a high energy requirement such as kidney, heart and skeletal muscles[3]. The above observations implicate the role of ESRRA in tumorigenesis and suggest that it could be an attractive target for anti-cancer therapy

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Conclusion