Acetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors

Linmao Sun, Yufeng Liu, Xinyu Guo, Tianming Cui, Chenghui Wu, Jie Tao, Cheng Cheng, Qi Chu, Changyong Ji, Xianying Li, Hongrui Guo, Shuhang Liang, Huanran Zhou, Shuo Zhou, Kun Ma, Ning Zhang, Jiabei Wang (), Yao Liu () and Lianxin Liu ()
Additional contact information
Linmao Sun: University of Science and Technology of China
Yufeng Liu: University of Science and Technology of China
Xinyu Guo: Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
Tianming Cui: University of Science and Technology of China
Chenghui Wu: University of Science and Technology of China
Jie Tao: Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
Cheng Cheng: University of Science and Technology of China
Qi Chu: University of Science and Technology of China
Changyong Ji: University of Science and Technology of China
Xianying Li: University of Science and Technology of China
Hongrui Guo: University of Science and Technology of China
Shuhang Liang: Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
Huanran Zhou: Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
Shuo Zhou: University of Science and Technology of China
Kun Ma: University of Science and Technology of China
Ning Zhang: Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
Jiabei Wang: University of Science and Technology of China
Yao Liu: University of Science and Technology of China
Lianxin Liu: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.

Date: 2024
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DOI: 10.1038/s41467-024-49573-7

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