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Molecular Cancer Research
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Cancer Genes and Networks

G9a Promotes Invasion and Metastasis of Non–Small Cell Lung Cancer through Enhancing Focal Adhesion Kinase Activation via NF-κB Signaling Pathway

Ting Sun, Keqiang Zhang, Rajendra P. Pangeni, Jun Wu, Wendong Li, Yong Du, Yuming Guo, Shyambabu Chaurasiya, Leonidas Arvanitis and Dan J. Raz
Ting Sun
1Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, California.
2Laboratory of Surgery, the General Hospital of Ningxia Medical University, Yinchuan, China.
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Keqiang Zhang
1Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, California.
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  • For correspondence: draz@coh.org kzhang@coh.org
Rajendra P. Pangeni
1Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, California.
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Jun Wu
3Division of Comparative Medicine, City of Hope National Medical Center, Duarte, California.
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Wendong Li
1Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, California.
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Yong Du
2Laboratory of Surgery, the General Hospital of Ningxia Medical University, Yinchuan, China.
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Yuming Guo
3Division of Comparative Medicine, City of Hope National Medical Center, Duarte, California.
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  • ORCID record for Yuming Guo
Shyambabu Chaurasiya
4Department of Surgery, City of Hope National Medical Center, Duarte, California.
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Leonidas Arvanitis
5Department of Pathology, City of Hope National Medical Center, Duarte, California.
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Dan J. Raz
1Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, California.
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  • For correspondence: draz@coh.org kzhang@coh.org
DOI: 10.1158/1541-7786.MCR-20-0557 Published March 2021
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Abstract

Potential roles of euchromatic histone methyltransferase 2 (EHMT2 or G9a) in invasion and metastasis are not well understood in non–small cell lung cancer (NSCLC). Here, we investigated the effect and underlying mechanisms of G9a and therapeutic implications of targeting G9a in the invasion and metastasis of NSCLC. Overexpression of G9a significantly enhanced in vitro proliferation and invasion, while knockdown of G9a drastically suppressed in vivo growth and metastasis of A549 and H1299 NSCLC cells. Knockdown or inhibition of G9a significantly decreased the expression of focal adhesion kinase (FAK) protein and activation of FAK pathway. In addition, defactinib, a potent FAK inhibitor, partially abolished the G9a-enhanced invasion in these NSCLC cells. Furthermore, targeting G9a was found to suppress NF-κB transcriptional activity in NSCLC cells through stabilizing NF-κB inhibitor alpha (IκBα), while an NF-κB inhibitor Parthenilide partially abolished the G9a-enhanced FAK activation, which suggests that G9a-enhanced invasion and activation of FAK is mediated by elevated NF-κB activity. Notably, a strong positive correlation between the IHC staining of G9a and phosphorylated FAK proteins was identified in H1299 xenografts and 159 cases of NSCLC tissues (R = 0.408).

Implications: The findings of this study strongly demonstrate that G9a may promote invasion and metastasis of NSCLC cells by enhancing FAK signaling pathway via elevating NF-κB transcriptional activity, indicating potential significance and therapeutic implications of these pathways in the invasion and metastasis of NSCLCs that overexpress G9a protein.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:429–40

  • Received June 24, 2020.
  • Revision received October 15, 2020.
  • Accepted December 2, 2020.
  • Published first December 9, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (3)
March 2021
Volume 19, Issue 3
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G9a Promotes Invasion and Metastasis of Non–Small Cell Lung Cancer through Enhancing Focal Adhesion Kinase Activation via NF-κB Signaling Pathway
Ting Sun, Keqiang Zhang, Rajendra P. Pangeni, Jun Wu, Wendong Li, Yong Du, Yuming Guo, Shyambabu Chaurasiya, Leonidas Arvanitis and Dan J. Raz
Mol Cancer Res March 1 2021 (19) (3) 429-440; DOI: 10.1158/1541-7786.MCR-20-0557

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G9a Promotes Invasion and Metastasis of Non–Small Cell Lung Cancer through Enhancing Focal Adhesion Kinase Activation via NF-κB Signaling Pathway
Ting Sun, Keqiang Zhang, Rajendra P. Pangeni, Jun Wu, Wendong Li, Yong Du, Yuming Guo, Shyambabu Chaurasiya, Leonidas Arvanitis and Dan J. Raz
Mol Cancer Res March 1 2021 (19) (3) 429-440; DOI: 10.1158/1541-7786.MCR-20-0557
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