GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner.
GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner.
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GNA13以棕榈酰化依赖性方式调节BCL2表达以及GCB-DLBCL细胞对BCL2抑制剂的敏感性
DOI：
10.1038/s41419-020-03311-1
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发表时间：
2021-01-09
影响因子：
9
通讯作者：
Ren R
中科院分区：
文献类型：
--
作者：
Xia Z;Zhang X;Liu P;Zhang R;Huang Z;Li D;Xiao X;Wu M;Ning N;Zhang Q;Zhang J;Liu M;Jiao B;Ren R
GNA13编码异源三聚体G蛋白的G蛋白α亚基之一，其抑制G蛋白偶联受体（GPCR）的信号，在生发中心B细胞样弥漫性大B细胞淋巴瘤（GCB-DLBCL）中经常发生突变，预后不良。由于GNA13的“不可用药”性质，这些患者的靶向治疗不可用。在本研究中，我们发现GNA13的棕榈酰化不仅调节其质膜定位，而且还调节GNA13的稳定性。它对于GNA13在GCB-DLBCL细胞中的肿瘤抑制功能是必需的。有趣的是，GNA13以棕榈酰化依赖性方式负调控GCB-DLBCL细胞中的BCL 2表达。一致地，在基于细胞的化学筛选中发现BCL 2抑制剂有效杀死GNA13缺陷型GCB-DLBCL细胞。此外，我们证明了通过靶向其棕榈酰化使GNA13失活增强了GCB-DLBCL对BCL 2抑制剂的敏感性。这些研究表明，GNA13的功能丧失突变是GCB-DLBCL的BCL 2抑制剂疗法的生物标志物，并且GNA13棕榈酰化是与BCL 2抑制剂联合疗法以用野生型GNA13治疗GCB-DLBCL的潜在靶标。
GNA13, encoding one of the G protein alpha subunits of heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR), is frequently mutated in germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) with poor prognostic outcomes. Due to the “undruggable” nature of GNA13, targeted therapy for these patients is not available. In this study, we found that palmitoylation of GNA13 not only regulates its plasma membrane localization, but also regulates GNA13’s stability. It is essential for the tumor suppressor function of GNA13 in GCB-DLBCL cells. Interestingly, GNA13 negatively regulates BCL2 expression in GCB-DLBCL cells in a palmitoylation-dependent manner. Consistently, BCL2 inhibitors were found to be effective in killing GNA13-deficient GCB-DLBCL cells in a cell-based chemical screen. Furthermore, we demonstrate that inactivating GNA13 by targeting its palmitoylation enhanced the sensitivity of GCB-DLBCL to the BCL2 inhibitor. These studies indicate that the loss-of-function mutation of GNA13 is a biomarker for BCL2 inhibitor therapy of GCB-DLBCL and that GNA13 palmitoylation is a potential target for combination therapy with BCL2 inhibitors to treat GCB-DLBCL with wild-type GNA13.
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影响因子：
64.8
作者：
Alizadeh, AA;Eisen, MB;Staudt, LM
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