Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition
Abstract 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 f...
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BMC
2024-12-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-024-03588-8 |
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| author | Xi Xie Baoyuan Zhang Donghe Li Jiaming Gao Jiaoyang Li Chenxuan Liu Yuqing Dan Pengfei Xu Lei Yan Xu Huang Rui Zhang Yunying Yao Wei Huang Jiawei Nie Xinru Wang Bo Jiao Ruibao Ren Ping Liu |
| author_facet | Xi Xie Baoyuan Zhang Donghe Li Jiaming Gao Jiaoyang Li Chenxuan Liu Yuqing Dan Pengfei Xu Lei Yan Xu Huang Rui Zhang Yunying Yao Wei Huang Jiawei Nie Xinru Wang Bo Jiao Ruibao Ren Ping Liu |
| author_sort | Xi Xie |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-f9028176821e487db361f19e681d8d22 |
| institution | Kabale University |
| issn | 1475-2867 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-f9028176821e487db361f19e681d8d222024-12-08T12:46:33ZengBMCCancer Cell International1475-28672024-12-0124111310.1186/s12935-024-03588-8Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibitionXi Xie0Baoyuan Zhang1Donghe Li2Jiaming Gao3Jiaoyang Li4Chenxuan Liu5Yuqing Dan6Pengfei Xu7Lei Yan8Xu Huang9Rui Zhang10Yunying Yao11Wei Huang12Jiawei Nie13Xinru Wang14Bo Jiao15Ruibao Ren16Ping Liu17Shanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineAbstract 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.https://doi.org/10.1186/s12935-024-03588-8CDK9Microtubule acetylationATAT1 |
| spellingShingle | Xi Xie Baoyuan Zhang Donghe Li Jiaming Gao Jiaoyang Li Chenxuan Liu Yuqing Dan Pengfei Xu Lei Yan Xu Huang Rui Zhang Yunying Yao Wei Huang Jiawei Nie Xinru Wang Bo Jiao Ruibao Ren Ping Liu Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition Cancer Cell International CDK9 Microtubule acetylation ATAT1 |
| title | Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition |
| title_full | Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition |
| title_fullStr | Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition |
| title_full_unstemmed | Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition |
| title_short | Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition |
| title_sort | suppression of microtubule acetylation mediates the anti leukemic effect of cdk9 inhibition |
| topic | CDK9 Microtubule acetylation ATAT1 |
| url | https://doi.org/10.1186/s12935-024-03588-8 |
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