Targeting the BCKDK/BCLAF1/MYC/HK2 axis to alter aerobic glycolysis and overcome Trametinib resistance in lung cancer

IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hao Wu, Jiajia Yang, Zixia Yang, Yawen Xiao, Ran Liu, Jing Jia, Xinrui Zhang, Yuting Zhang, Zheng Fu, Zhi Yao, Junqiang Lv
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引用次数: 0

Abstract

The protein branched-chain ketoacid dehydrogenase kinase (BCKDK), which regulates the metabolism of branched-chain amino acids, has recently been implicated in tumor progression. However, the role of BCKDK in lung cancer remains largely unexplored. In this study, we explored the mechanisms by which BCKDK influences lung cancer progression and contributes to drug resistance. By integrating single-cell RNA and bulk RNA sequencing data from lung cancer patients, we identified BCKDK as a novel gene related to malignant epithelial cells, involved in tumor initiation and associated with poor patient prognosis. Subsequently, through a series of molecular biology experiments, we demonstrated that BCKDK promotes aerobic glycolysis, Trametinib resistance, and tumor progression in lung cancer by upregulating MYC transcription. Mechanistically, BCKDK interacts with BCLAF1 to promote its phosphorylation at the serine 285 site. This modification facilitates BCLAF1 binding to the MYC promoter, thereby enhancing MYC transcription. Subsequently, elevated MYC levels upregulate hexokinase 2, promoting aerobic glycolysis and lung cancer progression. In addition, the elevated glycolysis product, lactate, promotes Trametinib resistance by upregulating the ABC transporters. Taken together, our data identify BCKDK as a novel regulator of aerobic glycolysis that promotes lung cancer progression and Trametinib resistance through the BCKDK/BCLAF1/MYC/HK2 axis. Targeting BCKDK in combination with Trametinib may offer a promising treatment for lung cancer.

Graphical representation of the BCKDK/BCLAF1/MYC/HK2 axis and its role in Trametinib resistance and lung cancer progression. Created with BioRender.com.

Abstract Image

靶向BCKDK/BCLAF1/MYC/HK2轴改变肺癌有氧糖酵解和克服曲美替尼耐药
调节支链氨基酸代谢的蛋白质支链酮酸脱氢酶激酶(BCKDK)最近被认为与肿瘤进展有关。然而,BCKDK在肺癌中的作用在很大程度上仍未被探索。在这项研究中,我们探讨了BCKDK影响肺癌进展和促进耐药的机制。通过整合来自肺癌患者的单细胞RNA和大量RNA测序数据,我们发现BCKDK是一个与恶性上皮细胞相关的新基因,参与肿瘤的发生并与患者预后不良相关。随后,通过一系列分子生物学实验,我们证明了BCKDK通过上调MYC转录促进肺癌的有氧糖酵解、曲美替尼耐药性和肿瘤进展。机制上,BCKDK与BCLAF1相互作用,促进其丝氨酸285位点的磷酸化。这种修饰促进BCLAF1与MYC启动子结合,从而增强MYC转录。随后,MYC水平升高上调己糖激酶2,促进有氧糖酵解和肺癌进展。此外,升高的糖酵解产物乳酸通过上调ABC转运蛋白促进曲美替尼耐药性。综上所述,我们的数据确定BCKDK是一种新的有氧糖酵解调节剂,通过BCKDK/BCLAF1/MYC/HK2轴促进肺癌进展和曲美替尼耐药。靶向BCKDK联合曲美替尼可能为肺癌提供一种有希望的治疗方法。BCKDK/BCLAF1/MYC/HK2轴的图形表达及其在曲美替尼耐药和肺癌进展中的作用创建与BioRender.com。
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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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