Acetylation of PHF5A Modulates Stress Responses and Colorectal Carcinogenesis through Alternative Splicing-Mediated Upregulation of KDM3A

Mol Cell. 2019 Jun 20;74(6):1250-1263.e6. doi: 10.1016/j.molcel.2019.04.009. Epub 2019 May 1.

Abstract

Alternative pre-mRNA-splicing-induced post-transcriptional gene expression regulation is one of the pathways for tumors maintaining proliferation rates accompanying the malignant phenotype under stress. Here, we uncover a list of hyperacetylated proteins in the context of acutely reduced Acetyl-CoA levels under nutrient starvation. PHF5A, a component of U2 snRNPs, can be acetylated at lysine 29 in response to multiple cellular stresses, which is dependent on p300. PHF5A acetylation strengthens the interaction among U2 snRNPs and affects global pre-mRNA splicing pattern and extensive gene expression. PHF5A hyperacetylation-induced alternative splicing stabilizes KDM3A mRNA and promotes its protein expression. Pathologically, PHF5A K29 hyperacetylation and KDM3A upregulation axis are correlated with poor prognosis of colon cancer. Our findings uncover a mechanism of an anti-stress pathway through which acetylation on PHF5A promotes the cancer cells' capacity for stress resistance and consequently contributes to colon carcinogenesis.

Keywords: HDAC6; KDM3A; PHF5A; RNA stability; acetylation; alternative splicing; cell proliferation; cellular stress; colorectal cancer; p300; spliceosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / deficiency
  • Acetylation
  • Alternative Splicing*
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms / diagnosis
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic*
  • HCT116 Cells
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
  • Jumonji Domain-Containing Histone Demethylases / genetics*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Nude
  • Prognosis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Ribonucleoprotein, U2 Small Nuclear / genetics
  • Ribonucleoprotein, U2 Small Nuclear / metabolism
  • Signal Transduction
  • Survival Analysis
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Xenograft Model Antitumor Assays
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism

Substances

  • PHF5A protein, human
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Ribonucleoprotein, U2 Small Nuclear
  • Trans-Activators
  • Acetyl Coenzyme A
  • Jumonji Domain-Containing Histone Demethylases
  • KDM3A protein, human
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor