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bioRxiv · 10.1101/2020.10.20.347401

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

Tian, X.·Ahsan, N.·Lulla, A.·Lev, A.·Abbosh, P.·Dicker, D.·Zhang, S.·El-Deiry, W.
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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.

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Tian, X., Ahsan, N., Lulla, A., Lev, A., Abbosh, P., Dicker, D., Zhang, S., El-Deiry, W.. 2020-10-20. P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9. https://doi.org/10.1101/2020.10.20.347401

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