The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis

Abstract

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1. The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A +/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.

Classic oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer

“…Gene ontology analysis for upregulated genes revealed an enrichment for epithelium development in addition to canonical c-Myc functions including regulation of cell proliferation and regulatory region nucleic acid binding (Figure 6D, right panel) while gene ontology analysis for downregulated of genes revealed an enrichment for neuronal associated genes (Figure 6D, left panel). These findings suggest c-Myc expression in ASCL1 expressing SCLC induces a transition to a more epithelial state and are consistent with the loss in neuroendocrine lineage state marker (Figure 5A), but did not reveal further specific mechanistic insights.Previous works have shown the negative regulation of ASCL1 by Notch signaling during lung development(36) and activation of Notch signaling in SCLC suppresses ASCL1 expression(20,37,38). Additionally, our SCLC transcriptional network analysis and Myc accessibility data revealed Notch pathway activation preferentially in c-Myc expressing tumors and cell lines (Figures 1E and 3C).…”

Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression

“…KDM5A gene is significantly amplified and overexpressed in various human cancers, such as ovarian cancer, small cell lung cancer and breast cancer [4,14,15].…”

The emerging role of KDM5A in human cancer

“…Lysine-specific demethylase 5A (KDM5A), also named Jumonji/ARID domain-containing protein 1A (JARID1A) or retinoblastoma-binding protein 2 (RBP2), originally reported as a retinoblastoma protein (RB) pocket domain-binding protein in 2001 [ 1 ], is a Fe(II)- and α-ketoglutaric acid (2OG)-dependent JmjC-containing oxygenase whose demethylase activity was first found in 2007 [ 2 ]. KDM5A can eliminate di- and tri-methyl moieties from the fourth lysine of histone 3 (H3K4me2/3), which leads to the activation or repression of transcription [ 3 – 13 ]. Additionally, the fusion gene NUP98-KDM5A, which is produced by rearrangement between NUP98 and KDM5A, mediates hematopoietic cell proliferation and alters myelo-erythropoietic differentiation via demethylating H3K4me2/3 [ 14 – 17 ].…”