HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness
HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness
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HDAC11通过LKB1/AMPK信号通路调节糖酵解以维持肝细胞癌干性
DOI：
10.1158/0008-5472.can-20-3044
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发表时间：
2021-04-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Yunshan
中科院分区：
文献类型：
--
作者：
Bi, Lei;Ren, Yidan;Wang, Yunshan
肝细胞癌（HCC）包含一个引起肿瘤复发、转移和耐化学性的癌症干细胞（CSC）亚群。组蛋白去乙酰化酶11 （HDAC11）介导多种免疫功能和代谢，但对其在HCCCSCs中的作用知之甚少。在本研究中，我们报道HDAC11在HCC中高表达，与疾病预后密切相关。在条件敲除小鼠模型中，HDAC11的缺失减少了肝细胞肿瘤的发生并延长了生存期。HDAC11的缺失通过促进启动子区域组蛋白乙酰化而增加LKB1的转录，从而激活AMPK信号通路并抑制糖酵解通路，进而抑制癌症的发生和HCC的进展。此外，HDAC11过表达降低了HCC对索拉非尼的敏感性。总的来说，这些数据表明HDAC11是激酶抵抗性HCC患者联合治疗的新靶点。意义：本研究发现HDAC11可抑制HCC中LKB1的表达，促进肿瘤的发生、进展和索拉非尼耐药，提示靶向HDAC11治疗HCC和克服激酶抑制剂耐药的潜力。
Hepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCCCSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinaseresistant HCC.Significance: This study finds that HDAC11 suppresses LKB1 expression in HCC to promote cancer stemness, progression, and sorafenib resistance, suggesting the potential of targeting HDAC11 to treat HCC and overcome kinase inhibitor resistance.