Shi Ping, Hoang-Minh Lan B, Tian Jia, Cheng Alice, Basrai Reemsha, Kalaria Neil, Lebowitz Joseph J, Khoshbouei Habibeh, Deleyrolle Loic P, Sarkisian Matthew R
Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Preston Wells Center for Brain Tumor Research, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Cancers (Basel). 2021 Apr 1;13(7):1644. doi: 10.3390/cancers13071644.
Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts glioma proliferation, but whether this effect is dependent on tumor cell primary cilia is unknown. We found that HDAC6 inhibitors ACY-1215 (1215) and ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse glioma cells. While both inhibitors triggered rapid increases in acetylated alpha-tubulin (aaTub) in the cytosol and led to increased frequencies of primary cilia, they unexpectedly reduced the levels of aaTub in the cilia. To test whether the antiproliferative effects of HDAC6 inhibitors are dependent on tumor cell cilia, we generated patient-derived glioma lines devoid of cilia through depletion of ciliogenesis genes ARL13B or KIF3A. At low concentrations, 1215 or 738 did not decrease the proliferation of cilia-depleted cells. Moreover, the differentiation of glioma cells that was induced by HDAC6 inhibition did not occur after the inhibition of cilia formation. These data suggest HDAC6 signaling at primary cilia promotes the proliferation of glioma cells by restricting their ability to differentiate. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia.
组蛋白去乙酰化酶6（HDAC6）是一个新出现的治疗靶点，与其他HDAC相比，它在胶质母细胞瘤中过表达。HDAC6催化α-微管蛋白的去乙酰化，并介导初级纤毛的解体，这是细胞周期进程所必需的过程。HDAC6抑制会破坏胶质瘤增殖，但这种效应是否依赖于肿瘤细胞初级纤毛尚不清楚。我们发现HDAC6抑制剂ACY-1215（1215）和ACY-738（738）抑制多种患者来源和小鼠胶质瘤细胞的增殖。虽然两种抑制剂都引发了细胞质中乙酰化α-微管蛋白（aaTub）的快速增加，并导致初级纤毛频率增加，但出乎意料的是，它们降低了纤毛中aaTub的水平。为了测试HDAC6抑制剂的抗增殖作用是否依赖于肿瘤细胞纤毛，我们通过耗尽纤毛发生基因ARL13B或KIF3A生成了无纤毛的患者来源胶质瘤细胞系。在低浓度下，1215或738不会降低无纤毛细胞的增殖。此外，在抑制纤毛形成后，HDAC6抑制诱导的胶质瘤细胞分化并未发生。这些数据表明，初级纤毛处的HDAC6信号通过限制胶质瘤细胞的分化能力来促进其增殖。令人惊讶的是，过表达HDAC6并没有缩短纤毛长度或降低有纤毛胶质瘤细胞的频率，这表明还需要其他因素来控制HDAC6介导的胶质瘤细胞纤毛解体。总的来说，我们的研究结果表明HDAC6通过初级纤毛促进胶质瘤细胞的增殖。
