KDM6A mediates the therapeutic efficacy of 2-DG combined with abemaciclib in head and neck squamous cell carcinoma

doi:10.12439/kqhm.1005-4979.2026.04.005

Abstract

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

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

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.

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.

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URL: https://journal06.magtech.org.cn/Jweb_joms/EN/10.12439/kqhm.1005-4979.2026.04.005

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

Figures/Tables 7

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

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

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

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

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

Figure 6 Validation of KDM6A knockout in SCC25 cells

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

References 28

[1]	Mody MD, Rocco JW, Yom SS, et al. Head and neck cancer[J]. Lancet, 2021, 398(10318): 2289-2299.
[2]	Johnson DE, Burtness B, Leemans CR, et al. Head and neck squamous cell carcinoma[J]. Nat Rev Dis Primers, 2020, 6: 92.
[3]	Porceddu SV, Daniels C, Yom SS, et al. Head and neck cancer international group (HNCIG) consensus guidelines for the delivery of postoperative radiation therapy in complex cutaneous squamous cell carcinoma of the head and neck (cSCCHN)[J]. Int J Radiat Oncol, 2020, 107(4): 641-651.
[4]	Adkins D, Ley J, Neupane P, et al. Palbociclib and cetuximab in platinum-resistant and in cetuximab-resistant human papillomavirus-unrelated head and neck cancer: A multicentre, multigroup, phase 2 trial[J]. Lancet Oncol, 2019, 20(9): 1295-1305.
[5]	Johnston SRD, Toi M, O'Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): Results from a preplanned interim analysis of a randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2023, 24(1): 77-90.
[6]	Navarro-Yepes J, Kettner NM, Rao XY, et al. Abemaciclib is effective in palbociclib-resistant hormone receptor-positive metastatic breast cancers[J]. Cancer Res, 2023, 83(19): 3264-3283.
[7]	Adkins DR, Lin JC, Sacco A, et al. Palbociclib and cetuximab compared with placebo and cetuximab in platinum-resistant, cetuximab-naïve, human papillomavirus-unrelated recurrent or metastatic head and neck squamous cell carcinoma: A double-blind, randomized, phase 2 trial[J]. Oral Oncol, 2021, 115: 105192.
[8]	Schoenwaelder N, Krause M, Freitag T, et al. Preclinical head and neck squamous cell carcinoma models for combined targeted therapy approaches[J]. Cancers, 2022, 14(10): 2484.
[9]	Duah E, Seligson ND, Persaud AK, et al. CDK4/6 and autophagy inhibitors synergize to suppress the growth of human head and neck squamous cell carcinomas[J]. Mol Carcinog, 2023, 62(8): 1201-1212.
[10]	Wang JK, Tsai MC, Poulin G, et al. The histone demethylase UTX enables RB-dependent cell fate control[J]. Genes Dev, 2010, 24(4): 327-332.
[11]	Schniewind I, Besso MJ, Klicker S, et al. Epigenetic targeting to overcome radioresistance in head and neck cancer[J]. Cancers, 2024, 16(4): 730.
[12]	Desilets A, Vos JL, Katabi N, et al. Phase 2 trial of regorafenib in recurrent/metastatic adenoid cystic carcinoma[J]. Clin Cancer Res, 2024, 30(23): 5281-5292.
[13]	Chen YH, Chen CH, Chien CY, et al. Overexpression of UTX promotes tumor progression in oral tongue squamous cell carcinoma patients receiving surgical resection: A case control study[J]. BMC Cancer, 2021, 21(1): 979.
[14]	Zhang DX, Zhao XH, Gao Y, et al. Inactivation of KDM6A promotes the progression of colorectal cancer by enhancing the glycolysis[J]. Eur J Med Res, 2024, 29(1): 310.
[15]	Lopez-Mejia IC, Lagarrigue S, Giralt A, et al. CDK4 phosphorylates AMPKα2 to inhibit its activity and repress fatty acid oxidation[J]. Mol Cell, 2024, 84(12): 2397.
[16]	Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN： A portal for facilitating tumor subgroup gene expression and survival analyses[J]. Neoplasia, 2017, 19(8): 649-658.
[17]	O'Sullivan B, Shah J. New TNM staging criteria for head and neck tumors[J]. Semin Surg Oncol, 2003, 21(1): 30-42.
[18]	Xiang X, Corsi GI, Anthon C, et al. Enhancing CRISPR-Cas9 gRNA efficiency prediction by data integration and deep learning[J]. Nat Commun, 2021, 12: 3238.
[19]	Kim N, Kim HK, Lee S, et al. Prediction of the sequence-specific cleavage activity of Cas9 variants[J]. Nat Biotechnol, 2020, 38(11): 1328-1336.
[20]	Ku BM, Yi SY, Koh J, et al. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma[J]. Oncotarget, 2016, 7(12): 14803-14813.
[21]	Xu QL, Zhang QZ, Ishida Y, et al. EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect[J]. Oncotarget, 2017, 8(6): 9557-9571.
[22]	Bollard J, Miguela V, Ruiz de Galarreta M, et al. Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma[J]. Gut, 2017, 66(7): 1286-1296.
[23]	Goyal RK, Chen H, Abughosh SM, et al. Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2—metastatic breast cancer in the United States: A SEER-medicare population-based study[J]. Cancer, 2023, 129(7): 1051-1063.
[24]	Swiecicki PL, Durm G, Bellile E, et al. A multi-center phaseⅡtrial evaluating the efficacy of palbociclib in combination with carboplatin for the treatment of unresectable recurrent or metastatic head and neck squamous cell carcinoma[J]. Invest New Drugs, 2020, 38(5): 1550-1558.
[25]	Hu QC, Peng JM, Jiang LB, et al. Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma[J]. Cell Death Dis, 2020, 11(10): 925.
[26]	Jeong EJ, Kim E, Jung KY, et al. WBP5 expression influences prognosis and treatment response in head and neck squamous cell carcinoma[J]. Cancers (Basel). 2025, 17(4): 587.
[27]	Chen J, Ji YK, Chen X, et al. KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC[J]. Cell Death Dis, 2025, 16: 777.
[28]	Chen X, Hu X, Chen J, et al. Inhibiting KDM6A phosphorylation suppresses glycolysis in oral squamous cell carcinoma[J]. Oral Dis, 2026, 32(3): 734-744.

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