Abstract
Histone deacetylase inhibitors (HDACis) are important drugs for cancer therapy, but the indistinct resistant mechanisms of solid tumor therapy greatly limit their clinical application. In this study we conducted HDACi-perturbated proteomics and phosphoproteomics analyses in HDACi-sensitive and -resistant cell lines using a tandem mass tag (TMT)-based quantitative proteomic strategy. We found that the ribosome biogenesis proteins MRTO4, PES1, WDR74 and NOP16 vital to tumorigenesis might regulate the tumor sensitivity to HDACi. By integrating HDACi-perturbated protein signature with previously reported proteomics and drug sensitivity data, we predicted and validated a series of drug combination pairs potentially to enhance the sensitivity of HDACi in diverse solid tumor. Functional phosphoproteomic analysis further identified the kinase PDK1 and ROCK as potential HDACi-resistant signatures. Overall, this study reveals the potential HDACi-resistant signatures and may provide promising drug combination strategies to attenuate the resistance of solid tumor to HDACi.
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Data availability
All mass spectrometry raw data have been deposited to the iProX Consortium with Project ID: IPX0006624000.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (32071432, 32171434, 82272943, 32322048), the Youth Science and Technology Talents in Shanghai Sail Plan of China (21YF1456000), Young Elite Scientists Sponsorship Program by CAST (2022QNRC001), Shanghai Rising-Star Program (22QA1411100), the Youth Innovation Promotion Association (CAS2021276) and the Sanofi Scholarship Program, Shanghai Committee of Science and Technology, China (21Y11913400), Guangdong High-level New R&D Institute, China (2019B090904008), Guangdong High-level Innovative Research Institute, China (2021B0909050003).
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MJT, BBH, DX and JYX conceived and supervised the project; BBH and JYX performed all the proteomics experiments; BBH, KM, JYX and RFF analyzed the data and performed the biological experiments; XLJ assisted with part of experiments; WSZ, LHZ and SL assisted with part of data analysis; BBH, KM, JYX and RFF wrote the manuscript; MJT and DX revised the manuscript. All authors approved the final version of the manuscript.
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Hao, Bb., Ma, K., Xu, Jy. et al. Proteomics analysis of histone deacetylase inhibitor-resistant solid tumors reveals resistant signatures and potential drug combinations. Acta Pharmacol Sin 45, 1305–1315 (2024). https://doi.org/10.1038/s41401-024-01236-5
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DOI: https://doi.org/10.1038/s41401-024-01236-5