Targeting NSD2-mediated SRC-3 liquid-liquid phase separation sensitizes bortezomib treatment in multiple myeloma.
Targeting NSD2-mediated SRC-3 liquid-liquid phase separation sensitizes bortezomib treatment in multiple myeloma.
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靶向NSD2介导的SRC-3液-液相分离使硼替佐米治疗多发性骨髓瘤变得敏感
DOI：
10.1038/s41467-021-21386-y
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发表时间：
2021-02-15
影响因子：
16.6
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Liu J;Xie Y;Guo J;Li X;Wang J;Jiang H;Peng Z;Wang J;Wang S;Li Q;Ye L;Zhong Y;Zhang Q;Liu X;Lonard DM;Wang J;O'Malley BW;Liu Z
化疗耐药的发生是多发性骨髓瘤(MM)临床治疗失败的主要原因，但导致这种化疗耐药的遗传和表观遗传学异常尚不清楚。在目前的研究中，我们发现类固醇受体辅活化子-3(SRC-3)的高表达与以博替佐米(BTZ)为基础的方案治疗的MM患者的复发/难治和不良预后相关。此外，在永生化细胞系中，高SRC-3增强了对蛋白酶体抑制物(PI)诱导的细胞凋亡的抵抗力。在携带t(4；14)易位的患者中过表达的组蛋白甲基转移酶NSD2或在对BTZ耐药的MM细胞中过表达的组蛋白甲基转移酶NSD2通过加强其液-液相分离以超常地修饰组蛋白H3赖氨酸36二甲基化(H3K36me2)修饰抗凋亡基因的启动子来协调升高的SRC-3。使用新开发的抑制剂SI-2靶向SRC-3或干扰其与NSD2的相互作用，可以敏化BTZ的治疗，并在体外和体内克服耐药性。综上所述，我们的发现阐明了SRC-3和NSD2在多发性骨髓瘤获得性耐药中的一种先前未知的协调作用，并提示SI-2可能有效地克服多发性骨髓瘤患者的耐药性。多发性骨髓瘤患者对蛋白酶体抑制剂Bortezomib产生获得性耐药的机制尚不清楚。在这里，作者证明了组蛋白甲基转移酶NSD2稳定了SRC-3蛋白的水平，促进了其相分离，并在某些基因启动子上改变了H3K36me2，导致了有利于骨髓瘤细胞对Bortezomib耐药的转录图谱。
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. The mechanisms behind acquired resistance to the proteasome inhibitor bortezomib in multiple myeloma remain to be elucidated. Here, the authors show that the histone methyltransferase NSD2 stabilized SRC-3 protein levels, promotes its phase separation and alters H3K36me2 at certain gene promoters resulting in a transcriptional profile that favors resistance of myeloma cells to bortezomib.
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影响因子：
20.3
作者：
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通讯作者：
Licht, Jonathan D.
影响因子：
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Licht JD
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作者：
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通讯作者：
Rajkumar, S. V.
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