Branched-chain amino acid catabolism breaks glutamine addiction to sustain hepatocellular carcinoma progression

Dongdong Yang; Haiying Liu; Yongping Cai; Kangyang Lu; Xiuying Zhong; Songge Xing; Wei Song; Yaping Zhang; Ling Ye; Xia Zhu; Ting Wang; Pinggen Zhang; Shi-Ting Li; Jiaqian Feng; Weidong Jia; Huafeng Zhang; Ping Gao

doi:10.1016/j.celrep.2022.111691

Branched-chain amino acid catabolism breaks glutamine addiction to sustain hepatocellular carcinoma progression

Cell Rep. 2022 Nov 22;41(8):111691. doi: 10.1016/j.celrep.2022.111691.

Authors

Dongdong Yang¹, Haiying Liu¹, Yongping Cai², Kangyang Lu², Xiuying Zhong³, Songge Xing⁴, Wei Song⁵, Yaping Zhang⁶, Ling Ye⁴, Xia Zhu², Ting Wang⁴, Pinggen Zhang⁴, Shi-Ting Li³, Jiaqian Feng⁴, Weidong Jia⁴, Huafeng Zhang⁷, Ping Gao⁸

Affiliations

¹ 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.
² Department of Pathology, School of Medicine, Anhui Medical University, Hefei 230032, China.
³ Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
⁴ 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.
⁵ Technical Center for Hefei Customs, Hefei 230022, China.
⁶ Thermo Fisher Scientific, Shanghai 201313, China.
⁷ 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. Electronic address: hzhang22@ustc.edu.cn.
⁸ Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China. Electronic address: pgao2@ustc.edu.cn.

PMID: 36417878
DOI: 10.1016/j.celrep.2022.111691

Abstract

Branched-chain amino acid (BCAA) catabolism is related to tumorigenesis. However, the underlying mechanism and specific contexts in which BCAAs affect tumor progression remain unclear. Here, we demonstrate that BCAA catabolism is activated in liver cancer cells without glutamine. Enhanced BCAA catabolism leads to BCAA-derived carbon and nitrogen flow toward nucleotide synthesis, stimulating cell-cycle progression and promoting cell survival. Mechanistically, O-GlcNAcylation increases under glutamine-deprivation conditions and stabilizes the PPM1K protein, leading to dephosphorylation of BCKDHA and enhanced decomposition of BCAAs. Dephosphorylation of BCKDHA and high expression of PPM1K promote tumorigenesis in vitro and in vivo and are closely related to the poor prognosis of clinical patients with hepatocellular carcinoma (HCC). Inhibition of BCAA and glutamine metabolism can further retard HCC growth in vivo. These results not only elucidate a mechanism by which BCAA catabolism affects tumorigenesis but also identify pBCKDHA and PPM1K as potential therapeutic targets and predictive biomarkers.

Keywords: CP: Cancer; CP: Metabolism; HCC progression; O-GlcNAcylation; branch-chain amino acid; glutamine-depravation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids, Branched-Chain / metabolism
Carcinogenesis
Carcinoma, Hepatocellular*
Glutamine / metabolism
Humans
Liver Neoplasms*

Substances

Glutamine
Amino Acids, Branched-Chain