Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide.

Scientific Reports
Shumpei TatenoYuki Yamaguchi

Abstract

Pomalidomide, a derivative of thalidomide, is an effective treatment for multiple myeloma. The drug exerts its effects through CRBN, a component of the E3 ubiquitin ligase complex CRL4CRBN. To search for novel factors involved in the anti-cancer activity of pomalidomide, we performed a genome-wide shRNA library screen and identified 445 genes as those affecting pomalidomide sensitivity. Genes encoding components of the ubiquitin-proteasome pathway, such as subunits of the CRL4CRBN complex, the COP9 signalosome, and the 26S proteasome, were among the pomalidomide-affecting genes. Karyopherin beta 1 (KPNB1) was identified as a novel pomalidomide-affecting gene. KPNB1 was required for the nuclear import of CRBN and for the CRBN-directed, pomalidomide-dependent degradation of a clinically relevant substrate, the transcription factor Aiolos. By contrast, the cytoplasmic translation factor GSPT1 was degraded following treatment with the thalidomide derivative CC-885 only when CRBN was present in the cytoplasm, indicating that subcellular distribution of CRBN is critical for the efficacy of thalidomide-based medications.

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Citations

Mar 4, 2021·Nature Reviews. Clinical Oncology·Max JanBenjamin L Ebert
Apr 24, 2021·Cell Chemical Biology·Predrag JevtićMichael Rapé
Jun 7, 2021·Biomarker Research·Shichao WangShaobing Gao
Aug 16, 2021·European Journal of Immunology·Cinzia FiondaAngela Santoni
Sep 24, 2021·Pflügers Archiv : European journal of physiology·Hyoung Kyu KimJin Han
Sep 30, 2021·Proceedings of the National Academy of Sciences of the United States of America·Thang Van Nguyen

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Methods Mentioned

BETA
neddylation
ubiquitination
transfection
nuclear translocation

Software Mentioned

Barcode Deconvoluter
PSORT
Database for Annotation , Visualization and Integrated Discove...
DAVID
Cellecta
PredictNLS

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