Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b interplay.
Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b interplay.
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DOI：
10.1186/s13045-016-0362-2
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发表时间：
2016-12-01
影响因子：
28.5
通讯作者：
Cippitelli M
中科院分区：
文献类型：
--
作者：
Abruzzese MP;Bilotta MT;Fionda C;Zingoni A;Soriani A;Vulpis E;Borrelli C;Zitti B;Petrucci MT;Ricciardi MR;Molfetta R;Paolini R;Santoni A;Cippitelli M
抗癌免疫应答可能有助于常规化疗后肿瘤的控制，并且不同的观察表明化疗剂可以诱导免疫应答，导致癌细胞死亡和免疫刺激副作用。越来越多的实验和临床证据强调了自然杀伤（NK）细胞在对多发性骨髓瘤（MM）的免疫应答中的重要性，并且能够增强NK细胞对MM的活性的联合疗法在治疗这种血液癌症方面显示出希望。乙酰化组蛋白布罗莫结构域和额外末端（BET）蛋白的表观遗传阅读器是基因表达的关键调节器。在癌症中，它们可以上调cMYC、IRF 4和BCL-2等关键癌基因的转录。此外，这些蛋白质的活性可以在癌症进展期间调节破骨细胞生成细胞因子的表达。在此，我们研究了BET溴结构域蛋白抑制对MM细胞中NK细胞活化配体表达的影响。使用从MM患者分离的5种MM细胞系[SKO-007（J3）、U266、RPMI-8226、阿普-1、JJN 3]和CD 138 + MM细胞来研究BET溴结构域抑制剂（BETi）的活性。（JQ 1和I-BET 151）和选择性BRD 4-降解剂蛋白水解靶向嵌合体（PROTAC）（ARV-825），使用流式细胞术、实时PCR、瞬时转染和脱粒测定，对几种NK细胞活化配体（NKG 2DLs和DNAM-1 Ls）的表达和功能进行研究。我们的研究结果表明，通过小分子抑制剂抑制BET蛋白或通过异源双功能PROTAC探针降解BET蛋白可增强人MM细胞系和原发性恶性浆细胞中云母（NKG 2D受体的配体）的表达，使骨髓瘤细胞更有效地激活NK细胞脱粒。值得注意的是，使用选择性CBP/EP 300布罗莫结构域抑制获得了类似的结果。从机制上讲，我们发现BETi介导的cMYC抑制与miR-125 b-5 p的上调和cMYC/miR-125 b-5 p靶基因IRF 4（云母的转录阻遏物）的下调相关。这些发现为BETi的免疫介导的抗肿瘤活性提供了新的见解，并进一步阐明了调节MM中NK细胞活化配体表达的分子机制。本文的在线版本（doi：10.1186/s13045-016-0362-2）包含补充材料，可供授权用户使用。
Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer. The epigenetic readers of acetylated histones bromodomain and extra-terminal (BET) proteins are critical regulators of gene expression. In cancer, they can upregulate transcription of key oncogenes such as cMYC, IRF4, and BCL-2. In addition, the activity of these proteins can regulate the expression of osteoclastogenic cytokines during cancer progression. Here, we investigated the effect of BET bromodomain protein inhibition, on the expression of NK cell-activating ligands in MM cells. Five MM cell lines [SKO-007(J3), U266, RPMI-8226, ARP-1, JJN3] and CD138+ MM cells isolated from MM patients were used to investigate the activity of BET bromodomain inhibitors (BETi) (JQ1 and I-BET151) and of the selective BRD4-degrader proteolysis targeting chimera (PROTAC) (ARV-825), on the expression and function of several NK cell-activating ligands (NKG2DLs and DNAM-1Ls), using flow cytometry, real-time PCR, transient transfections, and degranulation assays. Our results indicate that inhibition of BET proteins via small molecule inhibitors or their degradation via a hetero-bifunctional PROTAC probe can enhance the expression of MICA, a ligand of the NKG2D receptor, in human MM cell lines and primary malignant plasma cells, rendering myeloma cells more efficient to activate NK cell degranulation. Noteworthy, similar results were obtained using selective CBP/EP300 bromodomain inhibition. Mechanistically, we found that BETi-mediated inhibition of cMYC correlates with the upregulation of miR-125b-5p and the downregulation of the cMYC/miR-125b-5p target gene IRF4, a transcriptional repressor of MICA. These findings provide new insights on the immuno-mediated antitumor activities of BETi and further elucidate the molecular mechanisms that regulate NK cell-activating ligand expression in MM. The online version of this article (doi:10.1186/s13045-016-0362-2) contains supplementary material, which is available to authorized users.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
BET 溴结构域的抑制作为癌症药物发现的治疗策略
影响因子：
--
作者：
Fu LL;Tian M;Li X;Li JJ;Huang J;Ouyang L;Zhang Y;Liu B
通讯作者：
Liu B
影响因子：
16.6
作者：
Buckley, Dennis L.;Crews, Craig M.
通讯作者：
Crews, Craig M.
影响因子：
7.7
作者：
Conery, Andrew R.;Centore, Richard C.;Sims, Robert J., III
通讯作者：
Sims, Robert J., III
影响因子：
4.4
作者：
Fionda, Cinzia;Soriani, Alessandra;Cippitelli, Marco
通讯作者：
Cippitelli, Marco