Li Guoyin, Zhao Yukui, He Yubo, Qian Zhaoqiang, Li Xiaoyan, Song Zewen, Liu Zhiqiang
Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal University, Xi'an, China.
Fuxi Laboratory, Zhoukou Normal University, Zhoukou, China.
Front Oncol. 2025 Aug 25;15:1624370. doi: 10.3389/fonc.2025.1624370. eCollection 2025.
Gliomas, particularly glioblastoma, are aggressive brain tumors with poor prognosis and unmet therapeutic needs. Structural maintenance of chromosomes 4 (SMC4), a core component of the condensin complex, is dysregulated in multiple cancers, but its role in glioma metabolism and metastasis remains unclear.
Using integrated multi-omics analyses of glioma datasets, we assessed SMC4 expression and its correlation with clinical outcomes. Functional studies in U-251MG and LN229 glioma cells including CCK-8, EdU, cell cycle, Transwell, and wound-healing assays were combined with subcutaneous xenograft and tail-vein metastasis mouse models to evaluate SMC4's effects on proliferation, migration, invasion, and metastasis. ECAR/OCR and rescue experiments validated SMC4's role in glycolysis. Luciferase reporter and ChIP assays identified nuclear factor I A (NFIA) as an upstream transcriptional regulator of SMC4. A prognostic model (SRRS) was developed via LASSO regression and validated across cohorts.
SMC4 was significantly overexpressed in glioma tissues, with higher expression correlating with advanced tumor grades and poorer patient survival (AUC > 0.82). Mechanistically, SMC4 promoted G1/S cell cycle transition and proliferation /. It enhanced metastasis by activating TGF-β/SMAD signaling, evidenced by upregulated p-SMAD2/3, N-cadherin, SNAI1, and ZEB1, and increased lung metastases in mice. SMC4 also facilitated aerobic glycolysis by upregulating LDHA, shown via increased glucose uptake, lactate production, and ECAR, with rescue experiments confirming LDHA dependency. NFIA directly bound two motifs in the SMC4 promoter (-1379 bp and -354 bp), driving transcription, validated by dual-luciferase and ChIP assays. The SRRS, integrating 15 SMC4-coexpressed genes, stratified patients into high/low-risk groups with distinct survival (AUC > 0.7 for 1-, 3-, 5-year OS). A nomogram combining SRRS and clinical parameters improved accuracy (AUC > 0.88). Pharmacogenomic analysis linked SRRS to sensitivity to erlotinib and other agents.
SMC4 drives glioma progression through dual mechanisms TGF-β/SMAD-mediated metastasis and LDHA-dependent glycolysis regulated by NFIA. This extends beyond its known role in TGF-β activation by identifying NFIA as an upstream regulator and metabolic reprogramming as a novel function. The SRRS and nomogram provide robust tools for prognosis and personalized therapy, supporting the NFIA/SMC4 axis and downstream effectors as potential therapeutic targets for glioma.
胶质瘤，尤其是胶质母细胞瘤，是侵袭性脑肿瘤，预后较差且治疗需求未得到满足。染色体结构维持蛋白4（SMC4）是凝聚素复合体的核心成分，在多种癌症中表达失调，但其在胶质瘤代谢和转移中的作用仍不清楚。
通过对胶质瘤数据集进行综合多组学分析，我们评估了SMC4的表达及其与临床结果的相关性。在U-251MG和LN229胶质瘤细胞中进行功能研究，包括CCK-8、EdU、细胞周期、Transwell和伤口愈合试验，并结合皮下异种移植和尾静脉转移小鼠模型，以评估SMC4对增殖、迁移、侵袭和转移的影响。细胞外酸化率/氧耗率和挽救实验验证了SMC4在糖酵解中的作用。荧光素酶报告基因和染色质免疫沉淀试验确定核因子I A（NFIA）是SMC4的上游转录调节因子。通过LASSO回归开发了一种预后模型（SRRS），并在多个队列中进行了验证。
SMC4在胶质瘤组织中显著过表达，其较高表达与肿瘤分级较高和患者生存率较低相关（AUC>0.82）。从机制上讲，SMC4促进G1/S细胞周期转换和增殖。它通过激活TGF-β/SMAD信号增强转移，p-SMAD2/3、N-钙黏蛋白、SNAI1和ZEB1上调以及小鼠肺转移增加证明了这一点。SMC4还通过上调LDHA促进有氧糖酵解，这通过增加葡萄糖摄取、乳酸产生和细胞外酸化率得以体现，挽救实验证实了对LDHA的依赖性。NFIA直接结合SMC4启动子中的两个基序（-1379 bp和-354 bp），驱动转录，双荧光素酶和染色质免疫沉淀试验验证了这一点。整合15个与SMC4共表达基因的SRRS将患者分为高/低风险组，生存率不同（1年、3年、5年总生存率的AUC>0.7）。结合SRRS和临床参数的列线图提高了准确性（AUC>0.88）。药物基因组学分析将SRRS与对厄洛替尼和其他药物的敏感性联系起来。
SMC4通过TGF-β/SMAD介导的转移和由NFIA调节的LDHA依赖性糖酵解这两种机制驱动胶质瘤进展。通过将NFIA鉴定为上游调节因子并将代谢重编程确定为一种新功能，这扩展了其在TGF-β激活中的已知作用。SRRS和列线图为预后和个性化治疗提供了强大工具，支持将NFIA/SMC4轴及其下游效应器作为胶质瘤的潜在治疗靶点。
