Temozolomide (TMZ) is a commonly used chemotherapeutic agent for glioblastoma (GBM), but acquired drug resistance prevents its therapeutic efficacy. We investigated potential mechanisms underlying TMZ resistance and glycolysis in GBM cells through regulation by nuclear transcription factor Y subunit β (NFYB) of the oncogene serine hydroxymethyltransferase 2 (SHMT2). GBM U251 cells were transfected with NFYB-, SHMT2-, and the potential NFYB target histone deacetylase 5 (HDAC5)-related vectors. Glucose uptake and lactate production were measured with detection kits. CCK-8/colony formation, scratch, Transwell, and flow cytometry assays were performed to detect cell proliferation, migration, invasion, and apoptosis, respectively. The binding of NFYB to the HDAC5 promoter and the regulation of NFYB on HDAC5 promoter activity were detected with chromatin immunoprecipitation and dual-luciferase reporter assays, respectively. NFYB and HDAC5 were poorly expressed and SHMT2 was expressed at high levels in GBM U251 cells. NFYB overexpression or SHMT2 knockdown decreased glucose uptake, lactate production, proliferation, migration, and invasion and increased apoptosis and TMZ sensitivity of the cells. NFYB activated HDAC5 to inhibit SHMT2 expression. SHMT2 overexpression nullified the inhibitory effects of NFYB overexpression on glycolysis and TMZ resistance. Thus, NFYB may reduce tumorigenicity and TMZ resistance of GBM through effects on the HDAC5/SHMT2 axis.

中文翻译：

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NFYB 通过促进 HDAC5 介导的 SHMT2 转录抑制来增加胶质母细胞瘤的化疗敏感性。

替莫唑胺（TMZ）是胶质母细胞瘤（GBM）的常用化疗药物，但获得性耐药性阻碍了其治疗效果。我们通过癌基因丝氨酸羟甲基转移酶 2 (SHMT2) 的核转录因子 Y 亚基 β (NFYB) 的调节，研究了 GBM 细胞中 TMZ 耐药和糖酵解的潜在机制。GBM U251 细胞用 NFYB、SHMT2 和潜在的 NFYB 靶组蛋白脱乙酰酶 5 (HDAC5) 相关载体转染。使用检测试剂盒测量葡萄糖摄取和乳酸产生。进行CCK-8/集落形成、划痕、Transwell和流式细胞术测定分别检测细胞增殖、迁移、侵袭和凋亡。分别通过染色质免疫沉淀和双荧光素酶报告基因测定检测 NFYB 与 HDAC5 启动子的结合以及 NFYB 对 HDAC5 启动子活性的调节。GBM U251 细胞中 NFYB 和 HDAC5 表达较差，而 SHMT2 高水平表达。NFYB 过表达或 SHMT2 敲低会降低细胞的葡萄糖摄取、乳酸产生、增殖、迁移和侵袭，并增加细胞凋亡和 TMZ 敏感性。NFYB 激活 HDAC5 以抑制 SHMT2 表达。SHMT2 过表达消除了 NFYB 过表达对糖酵解和 TMZ 耐药的抑制作用。因此，NFYB 可能通过影响 HDAC5/SHMT2 轴来降低 GBM 的致瘤性和 TMZ 耐药性。