The Women's Hospital, Institute of Genetics, Zhejiang Provincial Key Laboratory of Genetic and Development Disorders, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Department of Neurosurgery, The Children's Hospital Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
Cell Mol Life Sci. 2023 Feb 10;80(3):61. doi: 10.1007/s00018-023-04708-9.
BRAF mutations have been found in gliomas which exhibit abnormal electrophysiological activities, implying their potential links with the ion channel functions. In this study, we identified the Drosophila potassium channel, Slowpoke (Slo), the ortholog of human KCNMA1, as a critical factor involved in dRaf glioma progression. Slo was upregulated in dRaf glioma. Knockdown of slo led to decreases in dRaf levels, glioma cell proliferation, and tumor-related phenotypes. Overexpression of slo in glial cells elevated dRaf expression and promoted cell proliferation. Similar mutual regulations of p-BRAF and KCNMA1 levels were then recapitulated in human glioma cells with the BRAF mutation. Elevated p-BRAF and KCNMA1 were also observed in HEK293T cells upon the treatment of 20 mM KCl, which causes membrane depolarization. Knockdown KCNMA1 in these cells led to a further decrease in cell viability. Based on these results, we conclude that the levels of p-BRAF and KCNMA1 are co-dependent and mutually regulated. We propose that, in depolarized glioma cells with BRAF mutations, high KCNMA1 levels act to repolarize membrane potential and facilitate cell growth. Our study provides a new strategy to antagonize the progression of gliomas as induced by BRAF mutations.
BRAF 突变已在表现出异常电生理活性的神经胶质瘤中被发现，这表明它们可能与离子通道功能有关。在这项研究中，我们鉴定出果蝇钾通道 Slowpoke（Slo），即人类 KCNMA1 的同源物，是参与 dRaf 神经胶质瘤进展的关键因素。Slo 在 dRaf 神经胶质瘤中上调。 slo 的敲低导致 dRaf 水平降低、神经胶质瘤细胞增殖和与肿瘤相关的表型减少。 slo 在神经胶质细胞中的过表达提高了 dRaf 的表达并促进了细胞增殖。然后，在具有 BRAF 突变的人类神经胶质瘤细胞中， recapitulated 了 p-BRAF 和 KCNMA1 水平的类似相互调节。在 20 mM KCl 处理引起膜去极化的情况下，HEK293T 细胞中也观察到升高的 p-BRAF 和 KCNMA1。在这些细胞中敲低 KCNMA1 导致细胞活力进一步下降。基于这些结果，我们得出结论，p-BRAF 和 KCNMA1 的水平是相互依赖和相互调节的。我们提出，在具有 BRAF 突变的去极化神经胶质瘤细胞中，高 KCNMA1 水平有助于使膜电位复极化并促进细胞生长。我们的研究为拮抗 BRAF 突变诱导的神经胶质瘤进展提供了一种新策略。
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