4.8 Article

PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer

Journal

CANCER RESEARCH
Volume 81, Issue 18, Pages 4696-4708

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-1114

Keywords

-

Categories

Funding

  1. NIH/NHLBI awards [R01HL149883, R01HL153122]
  2. NCI CCSG [P30 CA060553]
  3. NIH Office of Director [S10OD025194]
  4. National Resource for Translational and Developmental Proteomics [P41 GM108569]

Ask authors/readers for more resources

This study highlights the oncogenic function of the PAX9/NuRD complex epigenetic axis in human SCLC and suggests that reactivating primed enhancers may be a potential therapeutic strategy for treating SCLC expressing high levels of PAX9, offering insights into personalized therapeutic approaches targeting the PAX9-regulated network in small cell lung cancer.
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. Significance: A genome-wide screen in small cell lung cancer reveals PAX9/NuRD-mediated epigenetic enhancer silencing and tumor progression, supporting the development of novel personalized therapeutic approaches targeting the PAX9-regulated network.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available