TY - JOUR
T1 - RAS and PP2A activities converge on epigenetic gene regulation
AU - Aakula, Anna
AU - Sharma, Mukund
AU - Tabaro, Francesco
AU - Nätkin, Reetta
AU - Kamila, Jesse
AU - Honkanen, Henrik
AU - Schapira, Matthieu
AU - Arrowsmith, Cheryl
AU - Nykter, Matti
AU - Westermarck, Jukka
N1 - Publisher Copyright:
© 2023 Aakula et al.
PY - 2023/5
Y1 - 2023/5
N2 - 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/PP2Aregulated cellular processes.
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/PP2Aregulated cellular processes.
UR - http://www.scopus.com/inward/record.url?scp=85149427239&partnerID=8YFLogxK
U2 - 10.26508/lsa.202301928
DO - 10.26508/lsa.202301928
M3 - Article
C2 - 36858798
AN - SCOPUS:85149427239
SN - 2575-1077
VL - 6
JO - Life Science Alliance
JF - Life Science Alliance
IS - 5
M1 - 01928
ER -