2. Academic Validation
  3. Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon

Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon

  • Cell Mol Life Sci. 2024 Aug 13;81(1):349. doi: 10.1007/s00018-024-05390-1.
Busong Wang # 1,  Min Li # 1,  Dan Cao 1,  Qing Sun 1,  Wenjun Yu 1,  Jingjing Ma 2,  Haigang Ren 3,  Guoqiang Xu 4,  Liang Zhou 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu, China.
  • 2 Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, Jiangsu, China.
  • 3 Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu, China. rhg@suda.edu.cn.
  • 4 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu, China. gux2002@suda.edu.cn.
  • 5 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu, China. liangzhou@suda.edu.cn.
  • # Contributed equally.
PMID: 39136771 DOI: 10.1007/s00018-024-05390-1
Abstract

Multiple myeloma (MM) is the second most common hematological tumor in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. Len can recruit IKZF1 and IKZF3 to Cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 Ligase (CRL4), promote their ubiquitination and degradation, and finally inhibit the proliferation of myeloma cells. However, MM patients develop resistance to IMiDs over time, leading to disease recurrence and deterioration. To explore the possible approaches that may enhance the sensitivity of IMiDs to MM, in this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific Deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.

Keywords

Antimyeloma effect; BRCC36; Cell viability; Cereblon (CRBN); Lenalidomide; Multiple myeloma (MM).

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z