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.

• Authors: Matthew G Oser, Amin H Sabet, Wenhua Gao, Abhishek A Chakraborty, Anna C Schinzel, Rebecca B Jennings, Raquel Fonseca, Dennis M Bonal, Matthew A Booker, Abdallah Flaifel, Jesse S Novak, Camilla L Christensen, Hua Zhang, Zachary T Herbert, Michael Y Tolstorukov, Elizabeth J Buss, Kwok-Kin Wong, Roderick T Bronson, Quang-De Nguyen, Sabina Signoretti, William G Kaelin Jr
• Journal: Genes & development (Genes Dev) Vol. 33 Issue 23-24 Pg. 1718-1738 (12 01 2019) ISSN: 1549-5477 [Electronic] United States
• PMID: 31727771 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Oser et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• ASCL1 protein, human
• Basic Helix-Loop-Helix Transcription Factors
• Receptors, Notch
• Histone Demethylases
• KDM5A protein, human
• Retinoblastoma-Binding Protein 2

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors
• Cell Differentiation (genetics)
• Cell Line
• Cell Transformation, Neoplastic (genetics)
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic (genetics)
• Histone Demethylases (metabolism)
• Humans
• In Vitro Techniques
• Mice
• Neuroendocrine Cells (cytology, pathology)
• Receptors, Notch (physiology)
• Retinoblastoma-Binding Protein 2 (metabolism)
• Signal Transduction (genetics)
• Small Cell Lung Carcinoma (enzymology, physiopathology)