RT Journal Article
SR Electronic
T1 RAS and PP2A activities converge on epigenetic gene regulation
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202301928
DO 10.26508/lsa.202301928
VO 6
IS 5
A1 Anna Aakula
A1 Mukund Sharma
A1 Francesco Tabaro
A1 Reetta Nätkin
A1 Jesse Kamila
A1 Henrik Honkanen
A1 Matthieu Schapira
A1 Cheryl Arrowsmith
A1 Matti Nykter
A1 Jukka Westermarck
YR 2023
UL https://www.life-science-alliance.org/content/6/5/e202301928.abstract
AB 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 significant point of convergence for RAS hyperactivity and PP2A inhibition 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.