Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma.

Autor:	Xiong S; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Zhou J; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. csizjb@nus.edu.sg.; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. csizjb@nus.edu.sg.; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. csizjb@nus.edu.sg., Tan TK; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Chung TH; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Tan TZ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Toh SH; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Tang NXN; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Jia Y; Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China., See YX; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Fullwood MJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore., Sanda T; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Chng WJ; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. mdccwj@nus.edu.sg.; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. mdccwj@nus.edu.sg.; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. mdccwj@nus.edu.sg.; Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Health System (NUHS), Singapore, Singapore. mdccwj@nus.edu.sg.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2024 Aug 09; Vol. 15 (1), pp. 6810. Date of Electronic Publication: 2024 Aug 09.
DOI:	10.1038/s41467-024-50910-z
Abstrakt:	Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy. (© 2024. The Author(s).)
Databáze:	MEDLINE
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