HomeLatest HappeningsSMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma. (Cancer Res, May 2021)
SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma. (Cancer Res, May 2021)
Phyllis S Y Chong#1, Jing Yuan Chooi#2, Julia S L Lim23, Sabrina Hui Min Toh3, Tuan Zea Tan3, Wee-Joo Chng134
1Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. firstname.lastname@example.org email@example.com. 2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 3Cancer Science Institute of Singapore, National University of Singapore, Singapore. 4Department of Heamatology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex. RNA sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2-SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3. High levels of PTP4A3 maintained MYC expression and correlated with a 54-gene MYC signature in t(4;14) multiple myeloma. Importantly, this mechanism was druggable by targeting the bromodomain of SMARCA2 using the specific BET inhibitor PFI-3, leading to the displacement of NSD2 from PTP4A3 promoter and inhibiting t(4;14) myeloma cell viability. In vivo, treatment with PFI-3 reduced the growth of t(4;14) xenograft tumors. Together, our study reveals an interplay between histone-modifying enzymes and chromatin remodelers in the regulation of myeloma-specific genes that can be clinically intervened. SIGNIFICANCE: This study uncovers a novel, SWI/SNF-independent interaction between SMARCA2 and NSD2 that facilitates chromatin remodeling and transcriptional regulation of oncogenes in t(4;14) multiple myeloma, revealing a therapeutic vulnerability targetable by BET inhibition.