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

• DOI: 10.1016/j.neo.2021.01.004
• Publication Date: 2021-02-11T23:54:15Z
• Authors: Xiaobing Tian; Nagib Ahsan; Amriti Lulla; Avital Lev; Philip Abbosh; David T. Dicker; Shengliang Zhang; Wafik S. El-Deiry
• Keywords: 0301 basic medicine; Cancer therapy; Cell Survival; MAP Kinase Signaling System; Genes, myc; CDK9; Apoptosis; Models, Biological; Inhibitory Concentration 50; 03 medical and health sciences; PG3-Oc; Cell Line, Tumor; Humans; p53 pathway restoration; RC254-282; Original Research; Gene Editing; ERK1/2; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Endoplasmic Reticulum Stress; Activating Transcription Factor 4; Cyclin-Dependent Kinase 9; 3. Good health; Gene Expression Regulation, Neoplastic; Mutant p53; Mutation; CRISPR-Cas Systems; Tumor Suppressor Protein p53; Signal Transduction

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.