2-DG联合阿贝西利治疗头颈部鳞状细胞癌依赖KDM6A

doi:10.12439/kqhm.1005-4979.2026.04.005

摘要/Abstract

摘要：

目的：

探讨糖酵解抑制剂2-脱氧-D-葡萄糖（2-deoxy-D-glucose，2-DG）联合细胞周期依赖性激酶4/6（cyclin-dependent kinase 4/6，CDK4/6）抑制剂阿贝西利（abemaciclib）对头颈部鳞状细胞癌（head and neck squamous cell carcinoma，HNSCC）细胞存活的影响，并分析组蛋白赖氨酸去甲基化酶6A（histone lysine demethylase 6A，KDM6A）在其中的作用。

方法：

通过癌症基因组图谱（the Cancer Genome Atlas，TCGA）数据库和GEPIA2数据库分析HNSCC组织中CDK4/6的表达及其与糖酵解相关基因（HK1、HK2、GLUT1、GPI、PFKP、GAPDH、ALDOA、PGK1、PGAM1、ENO1、PKM及LDHA）表达的相关性。通过CCK-8法检测2-DG与阿贝西利单用或联合处理对SCC9、SCC25细胞活性的影响；采用蛋白质印迹法检测药物处理后KDM6A蛋白的表达；使用CRISPR-Cas9技术构建KDM6A敲除SCC25细胞（SCC25^ΔKDM6A），评价KDM6A缺失对联合用药抑制细胞存活的影响。

结果：

HNSCC组织中CDK4、CDK6 mRNA表达水平显著高于正常组织，且与糖酵解基因集表达呈正相关。CCK-8结果显示，2-DG联合阿贝西利较单药处理可进一步抑制HNSCC细胞存活；蛋白质印迹法结果表明，联合处理可提高SCC25细胞KDM6A蛋白表达水平。KDM6A敲除后，联合用药对SCC25细胞存活的抑制作用减弱。

结论：

2-DG 依赖KDM6A增强CDK4/6抑制剂对HNSCC的作用，为KDM6A缺失型HNSCC提供精准联合治疗新策略。

关键词: 头颈部鳞状细胞癌, 2-脱氧-D-葡萄糖, 阿贝西利, 糖酵解, CDK4/6, KDM6A

Abstract:

Objective:

To investigate the effect of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) combined with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor abemaciclib on the survival of head and neck squamous cell carcinoma (HNSCC) cells and to explore the role of histone lysine demethylase 6A (KDM6A) in this process.

Methods:

The expression levels of CDK4 and CDK6 in HNSCC tissues and their correlations with glycolysis-related genes (HK1, HK2, GLUT1, GPI, PFKP, GAPDH, ALDOA, PGK1, PGAM1, ENO1, PKM, and LDHA) were analyzed using the Cancer Genome Atlas (TCGA) and GEPIA2 databases. Cell proliferation following treatment with 2-DG and abemaciclib, either alone or in combination, was assessed in SCC9 and SCC25 cells using the CCK-8 assay. KDM6A protein expression after drug treatment was determined by Western blotting. KDM6A-knockout SCC25 cells (SCC25^ΔKDM6A) were generated using the CRISPR-Cas9 system to evaluate the effect of KDM6A deficiency on the antiproliferative activity of the combination therapy.

Results:

The mRNA expression levels of CDK4 and CDK6 were significantly higher in HNSCC tissues than in normal tissues and were positively correlated with the expression of glycolysis-related genes. The CCK-8 assay demonstrated that the combination of 2-DG and abemaciclib inhibited the survival of HNSCC cells more effectively than either agent alone. Western blotting showed that combination treatment increased KDM6A protein expression in SCC25 cells. Furthermore, KDM6A knockout attenuated the inhibitory effect of the combined treatment on SCC25 cell survival.

Conclusion:

2-DG enhances the antitumor efficacy of CDK4/6 inhibition in HNSCC through a KDM6A-dependent mechanism, providing a potential precision combination therapy strategy for KDM6A-deficient HNSCC.

Key words: head and neck squamous cell carcinoma, 2-deoxy-D-glucose, abemaciclib, glycolysis, CDK4/6, KDM6A

陈辛, 纪弈康, 胡鑫, 王旭. 2-DG联合阿贝西利治疗头颈部鳞状细胞癌依赖KDM6A[J]. 《口腔颌面外科杂志》, 2026, 36(4): 299-306.

CHEN Xin, JI Yikang, HU Xin, WANG Xu. KDM6A mediates the therapeutic efficacy of 2-DG combined with abemaciclib in head and neck squamous cell carcinoma[J]. Journal of Oral and Maxillofacial Surgery(CN), 2026, 36(4): 299-306.

https://journal06.magtech.org.cn/Jweb_joms/CN/Y2026/V36/I4/299

图/表 7

图1 CDK4和CDK6 mRNA在HNSCC组织与正常组织中的表达 A、B. CDK4和CDK6在HNSCC和正常组织中的mRNA表达水平；C、D. CDK4和CDK6在不同病理分级HNSCC和正常组织中的mRNA表达水平。***表示P<0.001，和正常组织比较。

Figure 1 CDK4 and CDK6 mRNA expression in HNSCC and normal tissues

图2 糖酵解基因集及各糖酵解相关基因在HNSCC组织与正常组织中的表达比较 A.糖酵解基因集在HNSCC组织和正常组织中的表达量比较；B.糖酵解相关基因在HNSCC组织（T：tumor）和正常组织（N：normal）中的表达量比较，***表示P<0.001，和正常组织比较。

Figure 2 Comparison of expression levels of the glycolytic gene set and individual glycolysis-related genes between HNSCC and normal tissues

图3 CDK4和CDK6 mRNA与糖酵解基因集的Pearson相关性散点图

Figure 3 Scatter plot of Pearson correlation between CDK4, CDK6 mRNA and glycolytic genes set

图4 阿贝西利与2-DG联用对SCC9细胞存活率的影响 *表示P<0.05，与300 nmol/L阿贝西利组比较。

Figure 4 Effect of abemaciclib combined with 2-DG on the cell viability of SCC9 cells

图5 阿贝西利联合2-DG对SCC25细胞KDM6A蛋白表达的影响 A.各组蛋白表达条带图；B.各组蛋白表达水平定量分析，*表示P<0.05，***表示P<0.001，和对照组比较。

Figure 5 Effect of abemaciclib combined with 2-DG on KDM6A protein expression in SCC25 cells

图6 KDM6A敲除SCC25细胞的验证 A. SCC25及SCC25^ΔKDM6A细胞中KDM6A蛋白表达条带图；B.蛋白相对表达量定量分析，***表示P<0.001，与SCC25细胞比较。

Figure 6 Validation of KDM6A knockout in SCC25 cells

图7 KDM6A敲除对2-DG联合阿贝西利抑制SCC25细胞存活的影响 A.阿贝西利与2-DG合用对SCC25细胞存活的影响；B.阿贝西利与2-DG合用对SCC25^ΔKDM6A细胞存活的影响。** 表示P<0.01，与300 nmol/L阿贝西利组比较。

Figure 7 Effect of KDM6A knockout on the inhibition of SCC25 cell viability by 2-DG combined with abemaciclib

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