P53-independent partial restoration of the p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9

Neoplasia. 2021 Mar;23(3):304-325. doi: 10.1016/j.neo.2021.01.004. Epub 2021 Feb 11.

Abstract

A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression.

Keywords: ATF4; CDK9; Cancer therapy; DR5; ERK1/2; MYC; Mutant p53; PG3-Oc; PUMA; p53 pathway restoration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics*
  • Activating Transcription Factor 4 / metabolism*
  • Apoptosis / drug effects
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase 9 / metabolism*
  • Endoplasmic Reticulum Stress
  • Gene Editing
  • Gene Expression Regulation, Neoplastic
  • Genes, myc
  • Humans
  • Inhibitory Concentration 50
  • MAP Kinase Signaling System
  • Models, Biological
  • Mutation*
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • ATF4 protein, human
  • Tumor Suppressor Protein p53
  • Activating Transcription Factor 4
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9