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Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple myeloma

Oncogene volume 39, pages 922–934 (2020)Cite this article

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Abstract

Multiple myeloma (MM) is still incurable despite the successful application of proteasome inhibitors in clinic. Bortezomib represents the most common chemotherapy for MM, whereas acquired drug resistance and eventually developed relapse remain the major obstruction. In the current study, we established bortezomib-resistant myeloma cell lines and screened gene expression profiles using single cell RNA-sequencing. Resistant MM cells exhibited increased clonogenic potential, specific metabolic, and epigenetic signatures, along with the self-renewal signaling characteristic of MM stem-like cells. Aberrant activation of hedgehog (Hh) signaling was correlated with drug resistance and stem cell-like transcriptional program. The key transcriptional factor GLI2 of the Hh pathway was restricted in the high acetylation and low ubiquitination states in bortezomib-resistant myeloma cells. Further investigation revealed that SIRT1 deacetylates and stabilizes GLI2 protein at lysine 757 and consequentially activates the Hh signaling, and itself serves as a direct target of Hh signaling to format a positive regulating loop. Using combination screening with an epigenetic compound library, we identified the SIRT1 specific inhibitor S1541 and S2804 had very obvious synergetic antimyeloma effect. Sirt1 inhibition could partially impeded the Hh pathway and conferred bortezomib sensitivity in vitro and in vivo. Notably, elevated SIRT1 level was also a prominent hallmark for the resistant myeloma cells, and this expression pattern was confirmed in myeloma patients, but independent of RAS/RAF mutations. Clinically, SIRT1 expression in patients with complete response was suppressed but elevated in relapsed patients, and retrospective analysis showed patients with higher SIRT1 expression had poorer outcomes. In conclusion, the cooperation of SIRT1 and Hh is an important mechanism of drug resistance in myeloma, and therapeutics combining SIRT1 inhibitors will sensitize myeloma cells to proteasome inhibitors.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81670201, 81870161, ZL), the Natural Science Foundation of Tianjin (16JCYBJC42600, ZL), the Talent Project of Tianjin Medical University (11601501/2016KJ0317, ZL), the Nanjing Key Medical Science and Technology Development Project (ZKX18023, QZ), and the Chuzhou Science and Technology Development Project (2018zd004, QZ).

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  1. These authors contributed equally: Ying Xie, Jing Liu

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, 300070, China

    Ying Xie, Jing Liu, Hongmei Jiang, Jingya Wang, Xin Li, Jingjing Wang, Shuai Zhu, Jing Guo & Zhiqiang Liu

  2. School of Medicine, Hunan Normal University, Changsha, Hunan, 410006, China

    Tao Li

  3. Department of Hematology, Myeloma Research Center of Beijing, Beijing Chao-Yang Hospital, Capital Medical University, Chaoyang, Beijing, 100020, China

    Yuping Zhong

  4. Department of Hematology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu, 210008, China

    Qiguo Zhang

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Contributions

ZL and TL contributed to the design of the experiments; YX and JL contributed to writing the paper; HJ, JW, XL, JW, SZ, and JG contributed to performing the experiments and statistical analyses; YZ and QZ provided the patient samples and clinical statistics.

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Correspondence to Zhiqiang Liu.

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Xie, Y., Liu, J., Jiang, H. et al. Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple myeloma. Oncogene 39, 922–934 (2020). https://doi.org/10.1038/s41388-019-1037-6

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