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Cancer Res. 2014 Dec 15;74(24):7333-43. doi: 10.1158/0008-5472.CAN-13-3572. Epub 2014 Dec 4.

H3K9 histone methyltransferase, KMT1E/SETDB1, cooperates with the SMAD2/3 pathway to suppress lung cancer metastasis.

Author information

  • 1VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China.
  • 2Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China.
  • 3Department of Basic Medical Sciences, Center for Cancer Research, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana.
  • 4Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
  • 5Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, Republic of China.
  • 6Department of Medical Research, Buddhist Dalin Tzu Chi Hospital, Chiayi, Taiwan, Republic of China.
  • 7Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
  • 8Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan, Republic of China.
  • 9Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China.
  • 10VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China. tytzeng@ym.edu.tw.

Abstract

Aberrant histone methylation is a frequent event during tumor development and progression. KMT1E (also known as SETDB1) is a histone H3K9 methyltransferase that contributes to epigenetic silencing of both oncogenes and tumor suppressor genes in cancer cells. In this report, we demonstrate that KMT1E acts as a metastasis suppressor that is strongly downregulated in highly metastatic lung cancer cells. Restoring KMT1E expression in this setting suppressed filopodia formation, migration, and invasive behavior. Conversely, loss of KMT1E in lung cancer cells with limited metastatic potential promoted migration in vitro and restored metastatic prowess in vivo. Mechanistic investigations indicated that KMT1E cooperates with the TGFβ-regulated complex SMAD2/3 to repress metastasis through ANXA2. Together, our findings defined an essential role for the KMT1E/SMAD2/3 repressor complex in TGFβ-mediated lung cancer metastasis.

©2014 American Association for Cancer Research.

PMID:
25477335
[PubMed - indexed for MEDLINE]
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