Xie Xi, Zhang Baoyuan, Li Donghe, Gao Jiaming, Li Jiaoyang, Liu Chenxuan, Dan Yuqing, Xu Pengfei, Yan Lei, Huang Xu, Zhang Rui, Yao Yunying, Huang Wei, Nie Jiawei, Wang Xinru, Jiao Bo, Ren Ruibao, Liu Ping
Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
International Center for Aging and Cancer, Hainan Medical College, Haikou, Hainan Province, China.
Cancer Cell Int. 2024 Dec 5;24(1):396. doi: 10.1186/s12935-024-03588-8.
Cyclin-dependent kinase 9 (CDK9) is a crucial component of transcription and potential target for anti-cancer therapies, particularly for hematological malignancies. However, the precise mechanisms underlying the therapeutic effects of CDK9 inhibitors remain not fully understood. Here, we found that inhibiting CDK9 either pharmacologically or through gene downregulation, significantly reduced the levels of α-tubulin protein in a time- and dose-dependent manner. We further discovered that CDK9 inhibition led to increased susceptibility of α-tubulin to proteasomal degradation due to reduced acetylation at lysine 40 (K40), an important modification for microtubule stability. An acetylation-mimicking mutant of α-tubulin mitigated the anti-tumor effects of CDK9 inhibition. Mechanically, we identified that CDK9 inhibition downregulated the expression of ATAT1, the acetyltransferase responsible for α-tubulin acetylation, further compromising microtubule stability. We also conducted in vivo studies in a leukemic xenograft model, where AZD4573 treatment led to significant tumor regression, decreased ATAT1 expression, and α-tubulin degradation. Our study unravels a novel molecular mechanism by which CDK9 inhibition disrupts α-tubulin stability and provides valuable insights for exploring effective treatment regimens involving CDK9 inhibitors.
细胞周期蛋白依赖性激酶9（CDK9）是转录的关键组成部分，也是抗癌治疗的潜在靶点，尤其是对血液系统恶性肿瘤。然而，CDK9抑制剂治疗效果的精确机制仍未完全了解。在此，我们发现，通过药理学方法或基因下调抑制CDK9，会以时间和剂量依赖性方式显著降低α-微管蛋白的水平。我们进一步发现，CDK9抑制导致α-微管蛋白对蛋白酶体降解的敏感性增加，这是由于赖氨酸40（K40）处的乙酰化减少，而K40乙酰化是微管稳定性的重要修饰。α-微管蛋白的乙酰化模拟突变体减轻了CDK9抑制的抗肿瘤作用。从机制上来说，我们确定CDK9抑制下调了负责α-微管蛋白乙酰化的乙酰转移酶ATAT1的表达，进一步损害了微管稳定性。我们还在白血病异种移植模型中进行了体内研究，其中AZD4573治疗导致肿瘤显著消退、ATAT1表达降低以及α-微管蛋白降解。我们的研究揭示了CDK9抑制破坏α-微管蛋白稳定性的一种新分子机制，并为探索涉及CDK9抑制剂的有效治疗方案提供了有价值的见解。
