JNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression

Jian Liu, Tianyuan Wang, Chad J. Creighton, San-Pin Wu, Madhumita Ray, Kyathanahalli S. Janardhan, Cynthia J. Willson, Sung-Nam Cho, Patricia D. Castro, Michael M. Ittmann, Jian-Liang Li, Roger J. Davis and Francesco J. DeMayo ()
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Jian Liu: National Institute of Environmental Health Sciences (NIEHS)
Tianyuan Wang: National Institute of Environmental Health Sciences (NIEHS)
Chad J. Creighton: Baylor College of Medicine (BCM)
San-Pin Wu: National Institute of Environmental Health Sciences (NIEHS)
Madhumita Ray: National Institute of Environmental Health Sciences (NIEHS)
Kyathanahalli S. Janardhan: Integrated Laboratory Systems
Cynthia J. Willson: Integrated Laboratory Systems
Sung-Nam Cho: BCM
Patricia D. Castro: BCM
Michael M. Ittmann: BCM
Jian-Liang Li: National Institute of Environmental Health Sciences (NIEHS)
Roger J. Davis: University of Massachusetts Medical School
Francesco J. DeMayo: National Institute of Environmental Health Sciences (NIEHS)

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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 ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα 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.

Date: 2019
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DOI: 10.1038/s41467-019-09843-1

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