OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB,Molecular Cell

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OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB
Molecular Cell ( IF 14.5 ) Pub Date : 2024-01-03 , DOI: 10.1016/j.molcel.2023.11.042
Wenhao Ma ₁ , Yuchen Sun ₁ , Ronghui Yan ₂ , Pinggen Zhang ₃ , Shengqi Shen ₄ , Hui Lu ₅ , Zilong Zhou ₅ , Zetan Jiang ₅ , Ling Ye ₅ , Qiankun Mao ₅ , Nanchi Xiong ₅ , Weidong Jia ₆ , Linchong Sun ₄ , Ping Gao ₄ , Huafeng Zhang ₇

Affiliation

Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China.
Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; Anhui Province Key Laboratory of Biomedical Aging Research, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China.
The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China; Anhui Province Key Laboratory of Biomedical Aging Research, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.

Metabolic reprogramming is an important feature of cancers that has been closely linked to post-translational protein modification (PTM). Lysine succinylation is a recently identified PTM involved in regulating protein functions, whereas its regulatory mechanism and possible roles in tumor progression remain unclear. Here, we show that OXCT1, an enzyme catalyzing ketone body oxidation, functions as a lysine succinyltransferase to contribute to tumor progression. Mechanistically, we find that OXCT1 functions as a succinyltransferase, with residue G424 essential for this activity. We also identified serine beta-lactamase-like protein (LACTB) as a main target of OXCT1-mediated succinylation. Extensive succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, ultimately leading to hepatocellular carcinoma (HCC) progression. In summary, this study establishes lysine succinyltransferase function of OXCT1 and highlights a link between HCC prognosis and LACTB K284 succinylation, suggesting a potentially valuable biomarker and therapeutic target for further development.

中文翻译：

OXCT1 作为琥珀酰转移酶发挥作用，通过琥珀酰化 LACTB 导致肝细胞癌

代谢重编程是癌症的一个重要特征，与翻译后蛋白修饰（PTM）密切相关。赖氨酸琥珀酰化是最近发现的一种参与调节蛋白质功能的 PTM，但其调节机制和在肿瘤进展中的可能作用尚不清楚。在这里，我们表明 OXCT1 是一种催化酮体氧化的酶，作为赖氨酸琥珀酰转移酶发挥作用，有助于肿瘤进展。从机制上讲，我们发现 OXCT1 作为琥珀酰转移酶发挥作用，残基 G424 对这种活性至关重要。我们还发现丝氨酸 β-内酰胺酶样蛋白（LACTB）是 OXCT1 介导的琥珀酰化的主要靶标。LACTB K284 的广泛琥珀酰化抑制其蛋白水解活性，导致线粒体膜电位和呼吸作用增加，最终导致肝细胞癌（HCC）进展。总之，本研究确定了 OXCT1 的赖氨酸琥珀酰转移酶功能，并强调了 HCC 预后与 LACTB K284 琥珀酰化之间的联系，表明进一步开发的潜在有价值的生物标志物和治疗靶点。

更新日期：2024-01-03

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