KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer

Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTX inactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express both ASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in an active chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone marks H3K4me2 and H3K27me3 and the histone demethylase KDM6A in primary mouse small cell lung cancer cells (SCLC) derived from SCLC genetically-engineered mouse models that are KDM6A WT (sgControl RPP) or KDM6A-Mutant (sgKdm6a RPP).