ΔNp63 regulates a common landscape of enhancer associated genes in non-small cell lung cancer

Marco Napoli, Sarah J. Wu, Bethanie L. Gore, Hussein A. Abbas, Kyubum Lee, Rahul Checker, Shilpa Dhar, Kimal Rajapakshe, Aik Choon Tan, Min Gyu Lee (), Cristian Coarfa () and Elsa R. Flores ()
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Marco Napoli: H. Lee Moffitt Cancer Center and Research Institute
Sarah J. Wu: H. Lee Moffitt Cancer Center and Research Institute
Bethanie L. Gore: H. Lee Moffitt Cancer Center and Research Institute
Hussein A. Abbas: H. Lee Moffitt Cancer Center and Research Institute
Kyubum Lee: H. Lee Moffitt Cancer Center and Research Institute
Rahul Checker: H. Lee Moffitt Cancer Center and Research Institute
Shilpa Dhar: University of Texas MD Anderson Cancer Center
Kimal Rajapakshe: Baylor College of Medicine
Aik Choon Tan: H. Lee Moffitt Cancer Center and Research Institute
Min Gyu Lee: University of Texas MD Anderson Cancer Center
Cristian Coarfa: Baylor College of Medicine
Elsa R. Flores: H. Lee Moffitt Cancer Center and Research Institute

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). ΔNp63, the p53 family member and p63 isoform, guides the maturation of these stem cells through the regulation of their self-renewal and terminal differentiation; however, the underlying mechanistic role regulated by ∆Np63 in lung cancer development has remained elusive. By utilizing a ΔNp63-specific conditional knockout mouse model and xenograft models of LUAD and LUSC, we found that ∆Np63 promotes non-small cell lung cancer by maintaining the lung stem cells necessary for lung cancer cell initiation and progression in quiescence. ChIP-seq analysis of lung basal cells, alveolar type 2 (AT2) cells, and LUAD reveals robust ∆Np63 regulation of a common landscape of enhancers of cell identity genes. Importantly, one of these genes, BCL9L, is among the enhancer associated genes regulated by ∆Np63 in Kras-driven LUAD and mediates the oncogenic effects of ∆Np63 in both LUAD and LUSC. Accordingly, high BCL9L levels correlate with poor prognosis in LUAD patients. Taken together, our findings provide a unifying oncogenic role for ∆Np63 in both LUAD and LUSC through the regulation of a common landscape of enhancer associated genes.

Date: 2022
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DOI: 10.1038/s41467-022-28202-1

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