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The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity.
He, Lin; Yu, Chunyu; Qin, Sen; Zheng, Enrun; Liu, Xinhua; Liu, Yanhua; Yu, Shimiao; Liu, Yang; Dou, Xuelin; Shang, Zesen; Wang, Yizhou; Wang, Yue; Zhou, Xuehong; Liu, Boning; Zhong, Yuping; Liu, Zhiqiang; Lu, Jin; Sun, Luyang.
Affiliation
  • He L; Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences
  • Yu C; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.
  • Qin S; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
  • Zheng E; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
  • Liu X; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.
  • Liu Y; Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences
  • Yu S; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
  • Liu Y; Peking University Institute of Hematology, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Beijing 100044, China.
  • Dou X; Peking University Institute of Hematology, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Beijing 100044, China.
  • Shang Z; Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China.
  • Wang Y; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
  • Wang Y; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal Un
  • Zhou X; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
  • Liu B; Peking University Institute of Hematology, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Beijing 100044, China.
  • Zhong Y; Department of Hematology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266003, China.
  • Liu Z; Department of Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • Lu J; Peking University Institute of Hematology, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Beijing 100044, China.
  • Sun L; Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences
Mol Cell ; 83(22): 4000-4016.e6, 2023 Nov 16.
Article in En | MEDLINE | ID: mdl-37935198
ABSTRACT
While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP component PSMD14 could not be explained by a selective inhibition of proteasomal activity. Here, we report that PSMD14 interacts with NSD2 on chromatin, independent of 19S RP. Functionally, PSMD14 acts as a histone H2AK119 deubiquitinase, facilitating NSD2-directed H3K36 dimethylation. Integrative genomic and epigenomic analyses revealed the functional coordination of PSMD14 and NSD2 in transcriptional activation of target genes (e.g., RELA) linked to myelomagenesis. Reciprocally, RELA transactivates PSMD14, forming a PSMD14/NSD2-RELA positive feedback loop. Remarkably, PSMD14 inhibitors enhance bortezomib sensitivity and fosters anti-myeloma synergy. PSMD14 expression is elevated in myeloma and inversely correlated with overall survival. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of PSMD14 as a therapeutic target to overcome the treatment limitation of myeloma.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Histones / Multiple Myeloma Limits: Humans Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2023 Document type: Article Publication country: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Histones / Multiple Myeloma Limits: Humans Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2023 Document type: Article Publication country: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA