Department of Neurosurgery and Neurosurgical Disease Research Centre, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Institute of Neurosciences of Guangzhou Medical University, Guangzhou, China.
J Neurochem. 2020 Jan;152(2):221-234. doi: 10.1111/jnc.14849. Epub 2019 Aug 25.
Histone deacetylase 6 (HDAC6) activity contributes to the malignant proliferation, invasion, and migration of glioma cells (GCs), but the molecular mechanisms underlying the processes remains elusive. Here, we reported that HDAC6 inhibition by Ricolinostat (ACY-1215) or CAY10603 led to a remarkable decrease in the phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, which preceded its suppressive effects on glioma cell growth. Further investigation showed that these effects resulted from HDAC6 inhibitor-induced suppression of MAPK kinase 7 (MKK7), which was identified to be critical for JNK activation and exerts the oncogenic roles in GCs. Selectively silencing HDAC6 by siRNAs had the same responses, whereas transient transfections expressing HDAC6 promoted MKK7 expression. Interestingly, by performing Q-PCR, HDAC6 inhibition did not cause a down-regulation of MKK7 mRNA level, whereas the suppressive effects on MKK7 protein can be efficiently blocked by the proteasomal inhibitor MG132. As a further test, elevating MKK7-JNK activity was sufficient to rescue HDAC6 inhibitor-mediated-suppressive effects on c-Jun activation and the malignant features. The suppression of both MKK7 expression and JNK/c-Jun activities was involved in the tumor-growth inhibitory effects induced by CAY10603 in U87-xenograft mice. Collectively, our findings provide new insights into the molecular mechanism of glioma malignancy regarding HDAC6 in the selective regulation of MKK7 expression and JNK/c-Jun activity. MKK7 protein stability critically depends on HDAC6 activity, and inhibition of HDAC6 probably presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c-Jun axis in GCs.
组蛋白去乙酰化酶 6（HDAC6）的活性有助于神经胶质瘤细胞（GCs）的恶性增殖、侵袭和迁移，但这些过程背后的分子机制仍不清楚。在这里，我们报道 Ricolinostat（ACY-1215）或 CAY10603 通过抑制 HDAC6 导致 c-Jun N 端激酶（JNK）和 c-Jun 的磷酸化显著减少，这先于其对神经胶质瘤细胞生长的抑制作用。进一步的研究表明，这些效应是由于 HDAC6 抑制剂诱导的丝裂原活化蛋白激酶激酶 7（MKK7）抑制所致，MKK7 对于 JNK 的激活至关重要，并在 GCs 中发挥致癌作用。通过 siRNAs 选择性沉默 HDAC6 具有相同的反应，而瞬时转染表达 HDAC6 则促进 MKK7 的表达。有趣的是，通过进行 Q-PCR，HDAC6 抑制不会导致 MKK7 mRNA 水平下调，而蛋白酶体抑制剂 MG132 可以有效地阻断对 MKK7 蛋白的抑制作用。作为进一步的测试，提高 MKK7-JNK 活性足以挽救 HDAC6 抑制剂对 c-Jun 激活和恶性特征的抑制作用。在 U87-xenograft 小鼠中，CAY10603 诱导的肿瘤生长抑制作用涉及对 MKK7 表达和 JNK/c-Jun 活性的抑制。总的来说，我们的研究结果为 HDAC6 选择性调节 MKK7 表达和 JNK/c-Jun 活性在胶质瘤恶性中的分子机制提供了新的见解。MKK7 蛋白稳定性取决于 HDAC6 活性，抑制 HDAC6 可能是抑制 MKK7/JNK/c-Jun 轴在 GCs 中致癌作用的潜在策略。
