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Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin.

Significance statement

Distant outgrowths (metastases) from primary lung tumors are major cause of cancer-related mortality in men and women world-wide. Herein, using a functional genomics strategy we analysed patient tumor transcriptomes, survival parameters, and performed genomic, cellular, molecular, and in vivo assays to identify non-metastatic 2 (NME2) as a key regulator of lung cancer spread. This study demonstrates regulation of focal adhesion signaling by NME2 is a key factor in control of metastatic dissemination of lung cancer cells. Based on this and other finding reported in the paper a novel angle for development of therapeutically important molecules that target NME2-vinculin signaling to control lung cancer metastasis is being pursued.

Figure legend: NME2 mediated vinculin (VCL) regulation is a key factor in decreased lung cancer metastasis. NME2 recruitment to VCL promoter results in low expression of VCL, which in turn induces cytoskeletal rearrangements that control cancer cell aggressiveness and metastasis.

Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Thakur RK1, Yadav VK2, Kumar A1, Singh A3, Pal K4, Hoeppner L4, Saha D3, Purohit G3, Basundra R1, Kar A1, Halder R1, Kumar P5, Baral A1, Kumar MJ6,Baldi A7, Vincenzi B8, Lorenzon L9, Banerjee R10, Kumar P1, Shridhar V11, Mukhopadhyay D4, Chowdhury S12. Nucleic Acids Res. 2014 ;42(18):11589-600.

Show Affiliations

1Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.

2G.N.R. Knowledge Centre for Genome Informatics, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.

3Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.

4Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.

5G.N.R. Knowledge Centre for Genome Informatics, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.

6Animal House, Centre For Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.

7Department of Biochemistry, Section of Pathology, Second University of Naples, Italy.

8University Campus Biomedico, Rome, Italy.

9Department of Surgery, University La Sapienza, Rome, Italy.

10Division of Lipid Science and Technology, Indian Institute of Chemical Technology, Hyderabad, India.

11Department of Experimental Pathology, Mayo Clinic Cancer Center, Rochester, MN, USA.

12Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India G.N.R. Knowledge Centre for Genome Informatics, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. [email protected]

 

Abstract

Tumor metastasis refers to spread of a tumor from site of its origin to distant organs and causes majority of cancer deaths. Although >30 metastasis suppressor genes (MSGs) that negatively regulate metastasis have been identified so far, two issues are poorly understood: first, which MSGs oppose metastasis in a tumor type, and second, which molecular function of MSG controls metastasis. Herein, integrative analyses of tumor-transcriptomes (n=382), survival data (n=530) and lymph node metastases (n=100) in lung cancer patients identified non-metastatic 2 (NME2) as akey MSG from a pool of >30 metastasis suppressors. Subsequently, we generated a promoter-wide binding map for NME2 using chromatin immunoprecipitation with promoter microarrays (ChIP-chip), and transcriptome profiling. We discovered novel targets of NME2 which are involved in focal adhesion signaling. Importantly, we detected binding of NME2 in promoter of focal adhesion factor, vinculin. Reduced expression of NME2 led to enhanced transcription of vinculin. In comparison, NME1, a close homolog of NME2, did not bind to vinculin promoter nor regulate its expression. In line, enhanced metastasis of NME2-depleted lung cancer cells was found in zebrafish and nude mice tumor models. The metastatic potential ofNME2-depleted cells was remarkably diminished upon selective RNA-i-mediated silencing of vinculin. Together, we demonstrate that reduced NME2 levels lead to transcriptional de-repression of vinculin and regulate lung  cancer metastasis.

© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

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