ALDOB/KAT2A interactions epigenetically modulate TGF-Î² expression and T cell functions in hepatocellular carcinogenesis

doi:10.1097/HEP.0000000000000704

	ALDOB/KAT2A interactions epigenetically modulate TGF-Î² expression and T cell functions in hepatocellular carcinogenesis
	Yin, Chunzhao1,2,3 ; Zhang, Cunzhen 4; Wang, Yongqiang 1; Liu, Guijun 1; Wang, Ningning 1; Liang, Ningning 1,3; Zhang, Lili 1; Tu, Qiaochu1,2 ; Lv, Jingwen 1; Jiang, Huimin 1; Ma, Haoran 1; Du, Chenxi1,2 ; Li, Min 1; He, Xuxiao 1; Chen, Shiting 1; Guo, Jiacheng 1; Li, Shengxian 5; Qin, Jun 1; Li, Nan 4; Tao, Yongzhen 1; Yin, Huiyong1,2,3,6
	2025
发表期刊	HEPATOLOGY (IF:12.9[JCR-2023],15.5[5-Year])
ISSN	0270-9139
EISSN	1527-3350
卷号	81 期号:1
发表状态	已发表
DOI	10.1097/HEP.0000000000000704
摘要	["Background and Aims: Cross talk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor HCC. However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC.","Approach and Results: We found that ALDOB downregulation was negatively correlated with CD8(+) T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-beta expression, thereby increasing the number of Treg cells and impairing the activity of CD8(+) T cells. Consistently, a combination of low ALDOB and high TGF-beta expression exhibited the worst overall survival for patients with HCC. More importantly, the simultaneous blocking of TGF-beta and programmed cell death (PD) 1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A, leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of lysine acetyltransferase 2A activity by small molecule inhibitors suppressed TGF-beta and HCC.","Conclusions: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-beta signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy."]
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收录类别	SCI
语种	英语
资助项目	National Key R&D Program of China["2018YFA0800301","2022YFC2503303"] ; National Natural Science Foundation of China["32150710522","32241017","92157108"]
WOS研究方向	Gastroenterology & Hepatology
WOS类目	Gastroenterology & Hepatology
WOS记录号	WOS:001379604900026
出版者	LIPPINCOTT WILLIAMS & WILKINS
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/470982
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_尹慧勇组生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Li, Nan; Tao, Yongzhen; Yin, Huiyong
作者单位	1.Chinese Acad Sci, Shanghai Inst Nutr & Hlth SINH, CAS Key Lab Nutr Metab & Food Safety Res, Shanghai, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 3.City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China 4.Shanghai Eastern Hepatobiliary Surg Hosp, Dept Hepat Surg 1, Ward 1, Shanghai, Peoples R China 5.Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Endocrinol & Metab, Shanghai, Peoples R China 6.City Univ Hong Kong, State Key Lab Marine Pollut SKLMP, Hong Kong, Peoples R China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Yin, Chunzhao,Zhang, Cunzhen,Wang, Yongqiang,et al. ALDOB/KAT2A interactions epigenetically modulate TGF-Î² expression and T cell functions in hepatocellular carcinogenesis[J]. HEPATOLOGY,2025,81(1).
APA	Yin, Chunzhao.,Zhang, Cunzhen.,Wang, Yongqiang.,Liu, Guijun.,Wang, Ningning.,...&Yin, Huiyong.(2025).ALDOB/KAT2A interactions epigenetically modulate TGF-Î² expression and T cell functions in hepatocellular carcinogenesis.HEPATOLOGY,81(1).
MLA	Yin, Chunzhao,et al."ALDOB/KAT2A interactions epigenetically modulate TGF-Î² expression and T cell functions in hepatocellular carcinogenesis".HEPATOLOGY 81.1(2025).