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KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE211165 | GEO | 2023/06/08

REPOSITORIES: GEO

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Small Cell Lung Cancer Subtype Plasticity is Regulated by KDM6A/UTX [RNA-Seq]

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KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer (atac batch2)

Project description:Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1,POU2F3, and Inflammatory. Initially SCLC subtypes were thought to be mutually exclusive, butrecent evidence shows intra-tumoral subtype heterogeneity and plasticity between subtypes.Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTXinactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express bothASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in anactive 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.

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Distinct Function for ASCL1 and NEUROD1 in Pulmonary Neuroendocrine Tumors (RNA-seq)

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