The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity.

IF 14.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2023-11-16 Epub Date: 2023-11-06 DOI:10.1016/j.molcel.2023.10.019

Lin He, Chunyu Yu, Sen Qin, Enrun Zheng, Xinhua Liu, Yanhua Liu, Shimiao Yu, Yang Liu, Xuelin Dou, Zesen Shang, Yizhou Wang, Yue Wang, Xuehong Zhou, Boning Liu, Yuping Zhong, Zhiqiang Liu, Jin Lu, Luyang Sun

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引用次数: 0

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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蛋白酶体组分PSMD14通过组蛋白去泛素酶活性驱动骨髓增生症。

虽然19S蛋白酶体调节颗粒（RP）抑制是治疗硼替佐米耐药骨髓瘤的一种有前途的新途径，但抑制19S RP组分PSMD14的抗肿瘤作用不能用选择性抑制蛋白酶体活性来解释。在这里，我们报道了PSMD14与染色质上的NSD2相互作用，独立于19S RP。在功能上，PSMD14作为组蛋白H2AK119去泛素酶，促进NSD2导向的H3K36二甲基化。综合基因组和表观基因组分析揭示了PSMD14和NSD2在与骨髓瘤相关的靶基因（如RELA）转录激活中的功能协调。反过来，RELA反式激活PSMD14，形成PSMD14/NSD2-RELA正反馈回路。值得注意的是，PSMD14抑制剂增强了硼替佐米的敏感性，并促进了抗骨髓瘤的协同作用。PSMD14在骨髓瘤中的表达升高，并且与总生存率呈负相关。我们的研究揭示了PSMD14作为表观遗传学调节因子和骨髓瘤驱动因子的一种未被重视的功能，支持将PSMD14用作克服骨髓瘤治疗局限性的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.