| Literature DB >> 33589584 |
Jing Liu1, Ying Xie1, Jing Guo1, Xin Li1, Jingjing Wang1, Hongmei Jiang1, Ziyi Peng1, Jingya Wang1, Sheng Wang1, Qian Li2, Linquan Ye3, Yuping Zhong4, Qiguo Zhang5, Xiaozhi Liu6, David M Lonard7, Jin Wang8, Bert W O'Malley9, Zhiqiang Liu10,11.
Abstract
Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.Entities:
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Year: 2021 PMID： 33589584 DOI： 10.1038/s41467-021-21386-y
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919