Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance

Xin Li, Sheng Wang, Ying Xie, Hongmei Jiang, Jing Guo, Yixuan Wang, Ziyi Peng, Meilin Hu, Mengqi Wang, Jingya Wang, Qian Li, Yafei Wang and Zhiqiang Liu ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37013-x

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