\u0394Np63 regulates a common landscape of enhancer associated genes in non-small cell lung cancer

Marco Napoli,Rahul Checker,Min Gyu Lee,Hussein A Abbas,Shilpa Dhar,Bethanie L Gore,Sarah J Wu,Aik Choon Tan,Kyubum Lee,Kimal Rajapakshe,Elsa R Flores,Cristian Coarfa

doi:10.1038/s41467-022-28202-1

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.

Highlights

Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC)
Because we found that ΔNp63 is required for the formation and progression of LUAD and lung squamous cell carcinoma (LUSC) and has a key role in maintaining tracheal basal cells, we asked whether ΔNp63 may regulate distal lung stem cells, where the cell of origin of LUAD reside
Interest has grown in understanding the regulation of genes associated with the most active enhancers, since these genes are the most highly expressed in the cell and are thought to play a key role in the biology of cancer

Summary

Introduction

Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). ChIP-seq analysis of lung basal cells, alveolar type 2 (AT2) cells, and LUAD reveals robust ΔNp63 regulation of a common landscape of enhancers of cell identity genes. One of these genes, BCL9L, is among the enhancer associated genes regulated by ΔNp63 in Kras-driven LUAD and mediates the oncogenic effects of ΔNp63 in both LUAD and LUSC. Due to similarities between tumour cells and stem cells in both signalling pathways and self-renewal abilities, cancer may originate from transformed stem cells[1] This hypothesis has been applied to the progenitor cell populations of the lung, including basal cells, alveolar type 2. We found that the ΔNp63 transcriptional signatures generated from either keratinocytes or LUSC and LUAD identified ΔNp63 as an oncogene in both NSCLC subtypes[13]

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