Refereed journal article or data article (A1)

RAS and PP2A activities converge on epigenetic gene regulation

List of AuthorsAakula Anna, Sharma Mukund, Tabaro Francesco, Nätkin Reetta, Kamila Jesse, Honkanen Henrik, Schapira Matthieu, Arrowsmith Cheryl, Nykter Matti, Westermarck Jukka

PublisherLife Science Alliance

Publication year2023

JournalLife Science Alliance

Journal name in sourceLIFE SCIENCE ALLIANCE

Journal acronymLIFE SCI ALLIANCE

Article number e202301928

Volume number6

Issue number5

Number of pages17




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RAS-mediated human cell transformation requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A). However, the phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, we discover that phosphosites co -regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co -regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168, and TP53BP1. We validate RAS-and PP2A-elicited regulation of HDAC1/2 chromatin recruitment, of RNF168-TP53BP1 interaction, and of gene expression. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter derepression and activation of oncogenic transcription. Transcriptional derepression by PP2A inhibition was associated with an increase in euchromatin and a decrease in global DNA methylation. Collectively, the results indicate that epigenetic protein complexes constitute a signifi-cant point of convergence for RAS hyperactivity and PP2A inhi-bition in cancer. Furthermore, the work provides an important resource for future studies focusing on phosphoregulation of epigenetic gene regulation in cancer and in other RAS/PP2A-regulated cellular processes.

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Last updated on 2023-30-06 at 13:19