Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism

Zhang, Qiangnu1,2,3; Wei, Teng2,4; Jin, Wen2,5; Yan, Lesen1,2; Shi, Lulin1,2; Zhu, Siqi1,2; Bai, Yu1,2; Zeng, Yuandi1,2; Yin, Zexin1,2; Yang, Jilin1,2; Zhang, Wenjian1,2; Wu, Meilong1,2; Zhang, Yusen1,2; Peng, Gongze1,2; Roessler, Stephanie6; Liu, Liping1,2

2024-02-01

10.1016/j.jhep.2023.10.024

JOURNAL OF HEPATOLOGY   影响因子和分区

0168-8278

1600-0641

Background & Aims: The role of solute carrier family 25 member 15 (SLC25A15), a critical component of the urea cycle, in hepatocellular carcinoma (HCC) progression remains poorly understood. This study investigated the impact of SLC25A15 on HCC progression and its mechanisms. Methods: We systematically investigated the function of SLC25A15 in HCC progression using large-scale data mining and cell, animal, and organoid models. Furthermore, we analyzed its involvement in reprogramming glutamine metabolism. Results: SLC25A15 expression was significantly decreased in HCC tissues, and patients with low SLC25A15 levels had a poorer prognosis. Hypoxia-exposed HCC cells or tissues had lower SLC25A15 expression. A positive correlation between HNF4A, a transcription factor suppressed by hypoxia, and SLC25A15 was observed in both HCC tissues and cells. Modulating HNF4A levels altered SLC25A15 mRNA levels. SLC25A15 upregulated SLC1A5, increasing glutamine uptake. The reactive metabolic pathway of glutamine was increased in SLC25A15-deficient HCC cells, providing energy for HCC progression through additional lipid synthesis. Ammonia accumulation due to low SLC25A15 levels suppressed the expression of OGDHL (oxoglutarate dehydrogenase L), a switch gene that mediates SLC25A15 deficiency -induced reprogramming of glutamine metabolism. SLC25A15-deficient HCC cells were more susceptible to glutamine deprivation and glutaminase inhibitors. Intervening in glutamine metabolism increased SLC25A15-deficient HCC cells' response to anti -PD -L1 treatment. Conclusion: SLC25A15 is hypoxia-responsive in HCC, and low SLC25A15 levels result in glutamine reprogramming through SLC1A5 and OGDHL regulation, promoting HCC progression and regulating cell sensitivity to anti -PD -L1. Interrupting the glutamine-derived energy supply is a potential therapeutic strategy for treating SLC25A15-deficient HCC. (c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Liver cancer Glutamine Hypoxia Urea cycle

SCI

英语

通讯

China Postdoctoral Science Foundation[2021M701426] ; GuangDong Basic and Applied Basic Research Foundation["2022A1515110283","2021A1515220059","2019A1515110149"] ; Shenzhen Science and Technology Innovation Commission Foundation["JCYJ20190806160412946","JCYJ20210324113008022"] ; National Natural Science Foundation of China["82002956","8140204"] ; Shenzhen Key Medical Discipline Construction Fund[SZXK015] ; Training Program for cultivating clinical physician -scientists of Shenzhen People's Hospital[SYWGSJCYJ202203]

Gastroenterology & Hepatology

Gastroenterology & Hepatology

WOS:001167865700001

ELSEVIER

CLINICAL MEDICINE

Web of Science

1.Jinan Univ, Clin Med Coll 2, Dept Gen Surg, Div Hepatobiliary & Pancreas Surg,Shenzhen Peoples, Shenzhen 518020, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China
3.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou 510632, Peoples R China
4.Jinan Univ, Clin Med Coll 2, Cytotherapy Lab, Shenzhen Peoples Hosp, Shenzhen 518020, Peoples R China
5.Jinan Univ, Clin Med Coll 2, Dept Neurol, Shenzhen Peoples Hosp, Shenzhen 518020, Peoples R China
6.Heidelberg Univ Hosp, Inst Pathol, D-69120 Heidelberg, Germany

Zhang, Qiangnu,Wei, Teng,Jin, Wen,et al. Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism[J]. JOURNAL OF HEPATOLOGY,2024,80(2).

Zhang, Qiangnu.,Wei, Teng.,Jin, Wen.,Yan, Lesen.,Shi, Lulin.,...&Liu, Liping.(2024).Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism.JOURNAL OF HEPATOLOGY,80(2).

Zhang, Qiangnu,et al."Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism".JOURNAL OF HEPATOLOGY 80.2(2024).