PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells

Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux issus de patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel le facteur nucléaire SET, en bloquant l'activité de la phosphatase PP2A, favorise la transcription des gènes essentiels à la croissance tumorale

Science Advances, Volume 10, Numéro 4, Page eadk6633, 2024, article en libre accès

Résumé en anglais

Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)–proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer. SET disrupts PP2A-A/C complex in the TSS-proximal regions, promoting oncogenic transcription in the pancreatic cancer.