Refereed journal article or data article (A1)
RAS and PP2A activities converge on epigenetic gene regulation
List of Authors: Aakula Anna, Sharma Mukund, Tabaro Francesco, Nätkin Reetta, Kamila Jesse, Honkanen Henrik, Schapira Matthieu, Arrowsmith Cheryl, Nykter Matti, Westermarck Jukka
Publisher: Life Science Alliance
Publication year: 2023
Journal: Life Science Alliance
Journal name in source: LIFE SCIENCE ALLIANCE
Journal acronym: LIFE SCI ALLIANCE
Article number: e202301928
Volume number: 6
Issue number: 5
Number of pages: 17
eISSN: 2575-1077
DOI: http://dx.doi.org/10.26508/lsa.202301928
URL: https://www.life-science-alliance.org/content/6/5/e202301928
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/179083143
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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