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

Ram Krishna Thakur, Vinod Kumar Yadav, Akinchan Kumar, Ankita Singh, Krishnendu Pal, Luke Hoeppner, Dhurjhoti Saha, Gunjan Purohit, Richa Basundra, Anirban Kar, Rashi Halder, Pankaj Kumar, Aradhita Baral, M. J Mahesh Kumar, Alfonso Baldi, Bruno Vincenzi, Laura Lorenzon, Rajkumar Banerjee, Praveen Kumar, Vijayalakshmi Shridhar & 2 others Debabrata Mukhopadhyay, Shantanu Chowdhury

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)11589-11600
Number of pages12
JournalNucleic Acids Research
Volume42
Issue number18
DOIs
StatePublished - Sep 12 2014

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Vinculin
Lung Neoplasms
Neoplasm Metastasis
Tumor Suppressor Genes
Neoplasms
Focal Adhesions
Gene Expression Profiling
Gene Pool
cell aggregation factors
Chromatin Immunoprecipitation
Zebrafish
Nude Mice
Lymph Nodes
RNA
Survival

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

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Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin. / Thakur, Ram Krishna; Yadav, Vinod Kumar; Kumar, Akinchan; Singh, Ankita; Pal, Krishnendu; Hoeppner, Luke; Saha, Dhurjhoti; Purohit, Gunjan; Basundra, Richa; Kar, Anirban; Halder, Rashi; Kumar, Pankaj; Baral, Aradhita; Kumar, M. J Mahesh; Baldi, Alfonso; Vincenzi, Bruno; Lorenzon, Laura; Banerjee, Rajkumar; Kumar, Praveen; Shridhar, Vijayalakshmi; Mukhopadhyay, Debabrata; Chowdhury, Shantanu.

In: Nucleic Acids Research, Vol. 42, No. 18, 12.09.2014, p. 11589-11600.

Research output: Contribution to journalArticle

Thakur, RK, Yadav, VK, Kumar, A, Singh, A, Pal, K, Hoeppner, L, Saha, D, Purohit, G, Basundra, R, Kar, A, Halder, R, Kumar, P, Baral, A, Kumar, MJM, Baldi, A, Vincenzi, B, Lorenzon, L, Banerjee, R, Kumar, P, Shridhar, V, Mukhopadhyay, D & Chowdhury, S 2014, 'Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin', Nucleic Acids Research, vol. 42, no. 18, pp. 11589-11600. https://doi.org/10.1093/nar/gku860
Thakur, Ram Krishna ; Yadav, Vinod Kumar ; Kumar, Akinchan ; Singh, Ankita ; Pal, Krishnendu ; Hoeppner, Luke ; Saha, Dhurjhoti ; Purohit, Gunjan ; Basundra, Richa ; Kar, Anirban ; Halder, Rashi ; Kumar, Pankaj ; Baral, Aradhita ; Kumar, M. J Mahesh ; Baldi, Alfonso ; Vincenzi, Bruno ; Lorenzon, Laura ; Banerjee, Rajkumar ; Kumar, Praveen ; Shridhar, Vijayalakshmi ; Mukhopadhyay, Debabrata ; Chowdhury, Shantanu. / Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin. In: Nucleic Acids Research. 2014 ; Vol. 42, No. 18. pp. 11589-11600.
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AU - Singh, Ankita

AU - Pal, Krishnendu

AU - Hoeppner, Luke

AU - Saha, Dhurjhoti

AU - Purohit, Gunjan

AU - Basundra, Richa

AU - Kar, Anirban

AU - Halder, Rashi

AU - Kumar, Pankaj

AU - Baral, Aradhita

AU - Kumar, M. J Mahesh

AU - Baldi, Alfonso

AU - Vincenzi, Bruno

AU - Lorenzon, Laura

AU - Banerjee, Rajkumar

AU - Kumar, Praveen

AU - Shridhar, Vijayalakshmi

AU - Mukhopadhyay, Debabrata

AU - Chowdhury, Shantanu

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N2 - 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.

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