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JNK(1/2) represses Lkb(1)-deficiency-induced lung squamous cell carcinoma progression

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Authors
Liu, Jian
Wang, Tianyuan
Creighton, Chad J.
Wu, San-Pin
Ray, Madhumita
Janardhan, Kyathanahalli S.
Willson, Cynthia J.
Cho, Sung-Nam
Castro, Patricia D.
Ittmann, Michael M.
UMass Chan Affiliations
Program in Molecular Medicine
Document Type
Journal Article
Publication Date
2019-05-14
Keywords
Non-small-cell lung cancer
Stress signalling
Cancer genomics
Prognostic markers
Cancer models
Cancer Biology
Cell Biology
Cellular and Molecular Physiology
Developmental Biology
Enzymes and Coenzymes

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Abstract
Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing DeltaNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKalpha and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.
Source

Nat Commun. 2019 May 14;10(1):2148. doi: 10.1038/s41467-019-09843-1. Link to article on publisher's site
DOI
10.1038/s41467-019-09843-1
Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41067
PubMed ID
31089135
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Link to Article in PubMed
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Copyright © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Copyright © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as Copyright © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.