ALDOB/KAT2A 相互作用从表观遗传学角度调节肝细胞癌变过程中的 TGF-β 表达和 T 细胞功能。

IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatology Pub Date : 2025-01-01 Epub Date: 2023-12-05 DOI:10.1097/HEP.0000000000000704
Chunzhao Yin, Cunzhen Zhang, Yongqiang Wang, Guijun Liu, Ningning Wang, Ningning Liang, Lili Zhang, Qiaochu Tu, Jingwen Lv, Huimin Jiang, Haoran Ma, Chenxi Du, Min Li, Xuxiao He, Shiting Chen, Jiacheng Guo, Shengxian Li, Jun Qin, Nan Li, Yongzhen Tao, Huiyong Yin
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引用次数: 0

摘要

背景目的:肿瘤细胞和免疫细胞之间的相互作用使肿瘤细胞能够逃避免疫监视并决定对免疫疗法的反应。先前的研究发现,肿瘤细胞中糖酵解酶果糖-1,6-二磷酸醛缩酶 B(ALDOB)的下调协调了代谢程序,有利于肝细胞癌(HCC)的发生。然而,肿瘤细胞中 ALDOB 的表达是否以及如何影响 HCC 中的肿瘤微环境仍是一个未知数:我们发现,在人类 HCC 肿瘤组织中,ALDOB 的下调与 CD8+ T 细胞浸润呈负相关,但处于衰竭状态。在肝脏特异性 ALDOB 基因敲除的小鼠或 ALDOB 基因敲除的皮下肿瘤模型中也观察到了类似的结果。此外,肿瘤细胞中 ALDOB 的缺乏会上调 TGF-β 的表达,从而增加 Treg 细胞的数量并损害 CD8+ T 细胞的活性。同样,低 ALDOB 和高 TGF-β 表达的组合显示出 HCC 患者最差的总生存率。更重要的是,用抗体同时阻断TGF-β和PD-1能抑制小鼠因ALDOB缺乏而诱发的肿瘤发生。进一步的机理实验证明,ALDOB 进入细胞核后与赖氨酸乙酰转移酶 2A(KAT2A)相互作用,导致抑制 H3K9 乙酰化,从而抑制 TGFB1 的转录。同样,小分子抑制剂抑制 KAT2A 的活性可抑制 TGF-β 和 HCC:我们的研究揭示了一种新的机制,即肿瘤细胞中的一种代谢酶通过表观遗传调节 TGF-β 信号,从而使癌细胞逃避免疫监视并影响其对免疫疗法的反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ALDOB/KAT2A interactions epigenetically modulate TGF-β expression and T cell functions in hepatocellular carcinogenesis.

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-β 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-β expression exhibited the worst overall survival for patients with HCC. More importantly, the simultaneous blocking of TGF-β 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-β and HCC.

Conclusions: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-β signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.

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来源期刊
Hepatology
Hepatology 医学-胃肠肝病学
CiteScore
27.50
自引率
3.70%
发文量
609
审稿时长
1 months
期刊介绍: HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.
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