2. Academic Validation
  3. The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity

The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity

  • Mol Cell. 2023 Nov 2:S1097-2765(23)00856-0. doi: 10.1016/j.molcel.2023.10.019.
Lin He 1,  Chunyu Yu 2,  Sen Qin 3,  Enrun Zheng 3,  Xinhua Liu 2,  Yanhua Liu 1,  Shimiao Yu 3,  Yang Liu 4,  Xuelin Dou 4,  Zesen Shang 5,  Yizhou Wang 3,  Yue Wang 6,  Xuehong Zhou 3,  Boning Liu 4,  Yuping Zhong 7,  Zhiqiang Liu 8,  Jin Lu 4,  Luyang Sun 9
Affiliations

Affiliations

  • 1 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, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
  • 4 Peking University Institute of Hematology, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Beijing 100044, China.
  • 5 Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China.
  • 6 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 University, Hangzhou 311121, China.
  • 7 Department of Hematology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266003, China.
  • 8 Department of Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 9 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, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China. Electronic address: [email protected].
PMID: 37935198 DOI: 10.1016/j.molcel.2023.10.019
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.

Keywords

19S regulatory particle; 26S proteasome; NSD2; PSMD14; RELA; bortezomib resistance; histone methylation; histone ubiquitination; multiple myeloma; t(4;14) translocation.

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