Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Sci Adv. 2024 Jan 26;10(4):eadk6633. doi: 10.1126/sciadv.adk6633.
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.
致癌转录的过度激活反映了癌细胞的表观遗传可塑性。Su(var)3-9、增强子 of zeste、Trithorax（SET）被描述为一种核因子，可刺激染色质模板的转录。然而，SET 依赖性转录的机制尚不清楚。在这里，我们发现 SET 和 CDK9 的过表达在多种癌细胞系中诱导了非常相似的转录组特征。SET 定位于转录起始位点（TSS）-近端区域，并支持 RNA 转录。SET 特异性结合 PP2A-C 亚基，并诱导 PP2A-A 亚基从 C 亚基排斥，这表明 SET 作为 TSS-近端区域的 PP2A-A/C 复合物破坏剂的作用。通过阻断 PP2A 活性，SET 协助 CDK9 维持 Pol II CTD 磷酸化并激活 mRNA 转录。我们的研究结果将 SET 定位为调节染色质 PP2A 活性的关键因素，促进了胰腺癌中的致癌转录。
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