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Histone acetylation insulator SET orchestrates PP2A inhibition and super-enhancer activation

He Xu, Di Wu, Jin Xu, Yubin Lei, Yalan Lei, Xianjun Yu, Si Shi
doi: https://doi.org/10.1101/2023.01.15.524091
He Xu
1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China;
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China;
3Shanghai Pancreatic Cancer Institute, Shanghai 200032, China;
4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China;
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Di Wu
1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China;
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China;
3Shanghai Pancreatic Cancer Institute, Shanghai 200032, China;
4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China;
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  • For correspondence: wudi@fudanpci.org diwu09@fudan.edu.cn yuxianjun@fudanpci.org shisi@fudanpci.org
Jin Xu
1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China;
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China;
3Shanghai Pancreatic Cancer Institute, Shanghai 200032, China;
4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China;
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Yubin Lei
5Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, Zhejiang Province, China. 310024;
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Yalan Lei
1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China;
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China;
3Shanghai Pancreatic Cancer Institute, Shanghai 200032, China;
4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China;
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Xianjun Yu
1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China;
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China;
3Shanghai Pancreatic Cancer Institute, Shanghai 200032, China;
4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China;
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  • For correspondence: wudi@fudanpci.org diwu09@fudan.edu.cn yuxianjun@fudanpci.org shisi@fudanpci.org
Si Shi
1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China;
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China;
3Shanghai Pancreatic Cancer Institute, Shanghai 200032, China;
4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China;
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  • For correspondence: wudi@fudanpci.org diwu09@fudan.edu.cn yuxianjun@fudanpci.org shisi@fudanpci.org
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Summary

Wide-spread growth-essential genes are hyper-transcribed in the pancreatic cancer cells. Searching for the factors that reprogram this abnormal transcription, we identified the nuclear oncogene SET that supported CDK9-induced and Pol II-mediated transcription. SET disrupted PP2A-A/C interaction via its C-terminal domains. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Meanwhile, as a histone acetylation insulator, SET mainly suppressed histone acetylation in the gene promoters but evaded enhancers. Massive super-enhancer associated genes, including the oncogene MET, were hence permitted to be transcribed by SET over-expression. Our findings position SET as a key factor that bridges histone acetylation and PP2A related transcription in cancer cells.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://data.mendeley.com/datasets/ys5kswxvw7/draft?a=3f82e213-d935-4e74-b88c-f5968b9417a1

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 17, 2023.
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Histone acetylation insulator SET orchestrates PP2A inhibition and super-enhancer activation
He Xu, Di Wu, Jin Xu, Yubin Lei, Yalan Lei, Xianjun Yu, Si Shi
bioRxiv 2023.01.15.524091; doi: https://doi.org/10.1101/2023.01.15.524091
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Histone acetylation insulator SET orchestrates PP2A inhibition and super-enhancer activation
He Xu, Di Wu, Jin Xu, Yubin Lei, Yalan Lei, Xianjun Yu, Si Shi
bioRxiv 2023.01.15.524091; doi: https://doi.org/10.1101/2023.01.15.524091

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