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Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance

Author

Listed:
  • Xin Li

    (Tianjin Medical University)

  • Sheng Wang

    (Tianjin Medical University)

  • Ying Xie

    (Tianjin Medical University)

  • Hongmei Jiang

    (Tianjin Medical University)

  • Jing Guo

    (Tianjin Medical University)

  • Yixuan Wang

    (Tianjin Medical University)

  • Ziyi Peng

    (Tianjin Medical University)

  • Meilin Hu

    (Tianjin Medical University School of Stomatology, Tianjin Medical University)

  • Mengqi Wang

    (Tianjin Medical University)

  • Jingya Wang

    (Tianjin Medical University)

  • Qian Li

    (Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer)

  • Yafei Wang

    (Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer)

  • Zhiqiang Liu

    (Tianjin Medical University)

Abstract

Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients.

Suggested Citation

  • Xin Li & Sheng Wang & Ying Xie & Hongmei Jiang & Jing Guo & Yixuan Wang & Ziyi Peng & Meilin Hu & Mengqi Wang & Jingya Wang & Qian Li & Yafei Wang & Zhiqiang Liu, 2023. "Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37013-x
    DOI: 10.1038/s41467-023-37013-x
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    References listed on IDEAS

    as
    1. Lei Zhang & Xinran Geng & Fangfang Wang & Jinshan Tang & Yu Ichida & Arishya Sharma & Sora Jin & Mingyue Chen & Mingliang Tang & Franklin Mayca Pozo & Wenxiu Wang & Janet Wang & Michal Wozniak & Xiaox, 2022. "53BP1 regulates heterochromatin through liquid phase separation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Kengo Watanabe & Kazuhiro Morishita & Xiangyu Zhou & Shigeru Shiizaki & Yasuo Uchiyama & Masato Koike & Isao Naguro & Hidenori Ichijo, 2021. "Cells recognize osmotic stress through liquid–liquid phase separation lubricated with poly(ADP-ribose)," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Jing Liu & Ying Xie & Jing Guo & Xin Li & Jingjing Wang & Hongmei Jiang & Ziyi Peng & Jingya Wang & Sheng Wang & Qian Li & Linquan Ye & Yuping Zhong & Qiguo Zhang & Xiaozhi Liu & David M. Lonard & Jin, 2021. "Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Lei Zhang & Xinran Geng & Fangfang Wang & Jinshan Tang & Yu Ichida & Arishya Sharma & Sora Jin & Mingyue Chen & Mingliang Tang & Franklin Mayca Pozo & Wenxiu Wang & Janet Wang & Michal Wozniak & Xiaox, 2022. "Author Correction: 53BP1 regulates heterochromatin through liquid phase separation," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
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    Cited by:

    1. Severin Lechner & Raphael R. Steimbach & Longlong Wang & Marshall L. Deline & Yun-Chien Chang & Tobias Fromme & Martin Klingenspor & Patrick Matthias & Aubry K. Miller & Guillaume Médard & Bernhard Ku, 2023. "Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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