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

Hyper-activation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. 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 over-expression 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 pancreatic cancer.