RAS介导的人类细胞转化需要抑制tumor suppressor蛋白磷酸酶2A（PP2A）。然而，在人类癌症中，RAS和PP2A活动收敛的磷酸化蛋白靶标和细胞过程尚未得到系统分析。在这里，我们发现RAS和PP2A共同调节的磷酸化位点在涉及表观遗传基因调控的蛋白质上富集。例如，RAS和PP2A共同调节HDAC1 / 2、KDM1A、MTA1 / 2、RNF168和TP53BP1等蛋白的相同磷酸化位点。我们验证了RAS和PP2A对HDAC1 / 2染色质招募，RNF168-TP53BP1相互作用和基因表达的调节作用。与它们在癌症中已知的协同作用一致，RAS激活和PP2A抑制导致表观基因报告解除抑制和致癌转录活化。 PP2A抑制引起的转录解除抑制与增加的EuHromatin和全局DNA甲基化降低相关。综上所述，这些结果表明，表观遗传蛋白复合物在RAS过度活化和PP2A抑制在癌症中的重要性点处有交汇。此外，该研究为今后研究癌症中和其他RAS/ PP2A调节的细胞过程中的表观基因调节的磷酸化调节提供了重要资源。©2023 Aakula等。

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.© 2023 Aakula et al.