IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37013-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37013-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-37013-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jin H. Yang & Hugo B. Brandão & Anders S. Hansen, 2023. "DNA double-strand break end synapsis by DNA loop extrusion," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Dongmei Wang & Tao Sun & Yuan Xia & Zhe Zhao & Xue Sheng & Shuying Li & Yuechan Ma & Mingying Li & Xiuhua Su & Fan Zhang & Peng Li & Daoxin Ma & Jingjing Ye & Fei Lu & Chunyan Ji, 2023. "Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Xiaoquan Wang & Youqiao Wang & Anqi Cao & Qinhong Luo & Daoyuan Chen & Weiqi Zhao & Jun Xu & Qinkai Li & Xianzhang Bu & Junmin Quan, 2023. "Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Daniel C. Carrettiero & Maria C. Almeida & Andrew P. Longhini & Jennifer N. Rauch & Dasol Han & Xuemei Zhang & Saeed Najafi & Jason E. Gestwicki & Kenneth S. Kosik, 2022. "Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37013-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.