ΔNp63 Regulates a Common Landscape of Enhancer Associated Genes in Non-Small Cell Lung Cancer

Authors

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
Elsa R Flores

Publication Date

2-1-2022

Journal

Nature Communications

DOI

10.1038/s41467-022-28202-1

PMID

35105868

PMCID

PMC8807845

PubMedCentral® Posted Date

2-1-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

no

Keywords

Adenocarcinoma of Lung, Animals, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Proliferation, Epithelium, Female, Gene Expression Regulation, Neoplastic, Humans, Lung, Lung Neoplasms, Male, Mice, Mice, Knockout, Cancer stem cells, Non-small-cell lung cancer

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.

Comments

This article has been corrected. See Nat Commun. 2022 Mar 25;13:1717.

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