School of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Cancer Res. 2021 Apr 15;81(8):2015-2028. doi: 10.1158/0008-5472.CAN-20-3044. Epub 2021 Feb 18.
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 HCC CSCs. 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 kinase-resistant 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.
肝细胞癌 (HCC) 包含一小部分癌症干细胞 (CSC)，这些细胞导致肿瘤复发、转移和化学抗性。组蛋白去乙酰化酶 11 (HDAC11) 介导多种免疫功能和代谢，但人们对其在 HCC CSC 中的作用知之甚少。在这项研究中，我们报告 HDAC11 在 HCC 中高度表达，与疾病预后密切相关。在条件性敲除小鼠模型中敲低 HDAC11 可减少肝细胞肿瘤发生并延长生存时间。HDAC11 的缺失通过促进其启动子区域的组蛋白乙酰化来增加 LKB1 的转录，从而激活 AMPK 信号通路并抑制糖酵解途径，进而抑制癌症干性和 HCC 进展。此外，HDAC11 的过表达降低了 HCC 对索拉非尼的敏感性。总之，这些数据表明 HDAC11 可作为激酶耐药 HCC 联合治疗的新靶点。意义：本研究发现 HDAC11 在 HCC 中抑制 LKB1 的表达以促进癌症干性、进展和索拉非尼耐药性，提示靶向 HDAC11 治疗 HCC 和克服激酶抑制剂耐药性的潜力。
