Wu Hao, Yang Jiajia, Yang Zixia, Xiao Yawen, Liu Ran, Jia Jing, Zhang Xinrui, Zhang Yuting, Fu Zheng, Yao Zhi, Lv Junqiang
Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, 300070, China.
Department of Medical Laboratory, Tianjin Hospital, Tianjin University, Jiefang Nan Road 406, Hexi District, Tianjin, 300211, China.
Cell Death Differ. 2025 May 29. doi: 10.1038/s41418-025-01531-6.
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.
蛋白质支链酮酸脱氢酶激酶（BCKDK）可调节支链氨基酸的代谢，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。在本研究中，我们探讨了BCKDK影响肺癌进展并导致耐药的机制。通过整合肺癌患者的单细胞RNA和大量RNA测序数据，我们确定BCKDK是一种与恶性上皮细胞相关的新基因，参与肿瘤起始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BCKDK通过上调MYC转录促进肺癌的有氧糖酵解、曲美替尼耐药和肿瘤进展。机制上，BCKDK与BCLAF1相互作用，促进其在丝氨酸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，升高的MYC水平上调己糖激酶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。综上所述，我们的数据确定BCKDK是有氧糖酵解的一种新型调节因子，它通过BCKDK/BCLAF1/MYC/HK2轴促进肺癌进展和曲美替尼耐药。联合曲美替尼靶向BCKDK可能为肺癌提供一种有前景的治疗方法。BCKDK/BCLAF1/MYC/HK2轴及其在曲美替尼耐药和肺癌进展中的作用的示意图。由BioRender.com创建。
