Abstract
Abnormalities in genetic and epigenetic modifications can lead to drastic changes in gene expression profiles that are associated with various cancer types. Small cell lung cancer (SCLC) is an aggressive and deadly form of lung cancer with limited effective therapies currently available. By utilizing a genome-wide CRISPR-Cas9 dropout screen in SCLC cells, we identified paired box protein 9 (PAX9) as an essential factor that is overexpressed in human malignant SCLC tumor samples and is transcriptionally driven by the BAP1/ASXL3/BRD4 epigenetic axis. Genome-wide studies revealed that PAX9 occupies distal enhancer elements and represses gene expression by restricting enhancer activity. In multiple SCLC cell lines, genetic depletion of PAX9 led to significant induction of a primed-active enhancer transition, resulting in increased expression of a large number of neural differentiation and tumor-suppressive genes. Mechanistically, PAX9 interacted and cofunctioned with the nucleosome remodeling and deacetylase (NuRD) complex at enhancers to repress nearby gene expression, which was reversed by pharmacologic HDAC inhibition. Overall, this study provides mechanistic insight into the oncogenic function of the PAX9/NuRD complex epigenetic axis in human SCLC and suggests that reactivation of primed enhancers may have potential therapeutic efficacy in treating SCLC expressing high levels of PAX9.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4696-4708 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 15 2021 |
Funding
B.D. Singer reports grants from NIH during the conduct of the study. E.T. Bartom reports grants from NIH during the conduct of the study and grants from NIH outside the submitted work. No disclosures were reported by the other authors. The authors would like to thank the following: Dr. Julien Sage for the kind gifts of mouse small cell lung cancer cell lines KP1 and KP3, and Dr. Feng Zhang for the kind gifts of the Px330 and lentiCRISPR v2 vectors. Dr. Benjamin D. Singer was supported by NIH/NHLBI awards R01HL149883 and R01HL153122. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569.
ASJC Scopus subject areas
- Oncology
- Cancer Research
