Glioma is a common type of malignant brain tumour with high mortality and relapse rate. However, the molecular mechanisms of glioma development have not been clarified. Differentially expressed genes in normal brain tissues and glioma tissues, low‐grade and high‐grade gliomas were screened out with GEO database analysis. We found that KLHDC8A (Kelch domain‐containing 8A) expression level was significantly increased in high‐grade glioma tissues and that high KLHDC8A expression was closely related with poor prognosis. Function assays indicated that KLHDC8A knockdown inhibited proliferation, migration and invasion, blocked the cell cycle and promoted apoptosis in glioma cells. Mechanistically, KLHDC8A regulated various functions in glioma by directly mediating Bcl2, BAX, p21, CDK2, MMP2 transcription and ERK and P38 MAPK activation. KLHDC8A overexpression enhances glioma tumorgenesis such as cell proliferation, migration and invasion. The ERK and P38 MAPK which activated by KLHDC8A overexpression could be reversed by U0126 and SB203580, respectively. Meanwhile, stimulation of lactate which produced by glycolysis is responsible for induction of KLHDC8A expression. Collectively, we demonstrated that KLHDC8A plays an important role in tumorgenesis of glioma, suggesting that it is a promising prognostic marker and a potential therapy target for the treatment of glioma.

中文翻译：

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乳酸诱导的KLHDC8A（含Kelch域的8A）上调有助于人类神经胶质瘤细胞的增殖，迁移和凋亡。

胶质瘤是一种常见的恶性脑肿瘤，具有很高的死亡率和复发率。但是，胶质瘤发展的分子机制尚未阐明。用GEO数据库分析筛选出正常脑组织和神经胶质瘤组织，低度和高度神经胶质瘤中差异表达的基因。我们发现，高级别胶质瘤组织中KLHDC8A（含Kelch域的8A）表达水平显着升高，而KLHDC8A的高表达与不良预后密切相关。功能测定表明，KLHDC8A抑制可抑制神经胶质瘤细胞的增殖，迁移和侵袭，阻断细胞周期并促进其凋亡。从机制上讲，KLHDC8A通过直接介导Bcl2，BAX，p21，CDK2，MMP2转录以及ERK和P38 MAPK激活来调节神经胶质瘤的各种功能。KLHDC8A过表达增强神经胶质瘤的肿瘤发生，例如细胞增殖，迁移和侵袭。KLHDC8A过表达激活的ERK和P38 MAPK可以分别被U0126和SB203580逆转。同时，通过糖酵解产生的乳酸刺激引起KLHDC8A表达的诱导。集体地，我们证明了KLHDC8A在神经胶质瘤的肿瘤发生中起重要作用，表明它是有希望的预后标志物和治疗神经胶质瘤的潜在治疗靶标。糖酵解产生的乳酸刺激可诱导KLHDC8A表达。集体地，我们证明了KLHDC8A在神经胶质瘤的肿瘤发生中起重要作用，表明它是有希望的预后标志物和治疗神经胶质瘤的潜在治疗靶标。糖酵解产生的乳酸刺激可诱导KLHDC8A表达。集体地，我们证明了KLHDC8A在神经胶质瘤的肿瘤发生中起重要作用，表明它是有希望的预后标志物和治疗神经胶质瘤的潜在治疗靶标。