title: Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin.
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 a key 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 of NME2-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.
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.
authors.forename: Ram Krishna
authors.initials: RK
authors.lastname: Thakur
authors.affiliation: G.N.R. Knowledge Centre for Genome Informatics, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.
authors.forename: Vinod Kumar
authors.initials: VK
authors.lastname: Yadav
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.
authors.forename: Akinchan
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Proteomics 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.
authors.forename: Ankita
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Pal
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Hoeppner
authors.affiliation: Proteomics 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.
authors.forename: Dhurjhoti
authors.initials: D
authors.lastname: Saha
authors.affiliation: Proteomics 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.
authors.forename: Gunjan
authors.initials: G
authors.lastname: Purohit
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Basundra
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Kar
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.
authors.forename: Rashi
authors.initials: R
authors.lastname: Halder
authors.affiliation: 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.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.
authors.forename: Aradhita
authors.initials: A
authors.lastname: Baral
authors.affiliation: Animal House, Centre For Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
authors.forename: M J Mahesh
authors.initials: MJ
authors.lastname: Kumar
authors.affiliation: Department of Biochemistry, Section of Pathology, Second University of Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.affiliation: University Campus Biomedico, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.affiliation: Department of Surgery, University La Sapienza, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lorenzon
authors.affiliation: Division of Lipid Science and Technology, Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Banerjee
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Experimental Pathology, Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.affiliation: Proteomics 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 shantanuc@igib.res.in.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D022001:Focal Adhesions / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D008819:Mice, Nude; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D016596:Vinculin / Q000096:biosynthesis / Q000235:genetics*; D015027:Zebrafish
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; D016596:Vinculin; C517940:NME2 protein, human