Steroid receptor coactivator-3 is a pivotal target of gambogic acid in B-cell Non-Hodgkin lymphoma and an inducer of histone H3 deacetylation
Steroid receptor coactivator-3 is a pivotal target of gambogic acid in B-cell Non-Hodgkin lymphoma and an inducer of histone H3 deacetylation
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类固醇受体辅激活因子 3 是 B 细胞非霍奇金淋巴瘤中藤黄酸的关键靶点，也是组蛋白 H3 脱乙酰化的诱导剂
DOI：
10.1016/j.ejphar.2016.06.048
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发表时间：
2016
影响因子：
5
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Zhao Zichu;Zhang Xia;Yi Sha;Hu Jingyu;Ruan Jun;Zhao Fei;Cui Guohui;Fang Jun;Chen Yan;Wen Lu;Fang J;Chen Y
藤黄酸（Gambogic acid， GA）是一种从藤黄中提取的有效成分，已被证实对许多癌细胞具有有效的抗肿瘤作用。然而，其在淋巴瘤中的作用，特别是在b细胞非霍奇金淋巴瘤（NHL）中的作用尚不清楚。类固醇受体共激活因子-3 （SRC-3）的扩增和/或过表达已在多种肿瘤中被检测到，并证实其在这些肿瘤的发生、进展、转移和治疗耐药中起关键作用。然而，没有临床数据揭示SRC-3的过表达及其在b细胞NHL中的作用。在本研究中，我们证明了GA在b细胞NHL中的抗肿瘤作用，包括细胞生长抑制、G1/S期细胞周期阻滞和凋亡。我们还证实SRC-3在b细胞NHL细胞系和患者淋巴结样本中都过表达。过表达的SRC-3是GA的中心药物靶点，其下调随后调控下游基因表达，最终导致细胞凋亡。沉默SRC-3可降低Bcl-2、Bcl-6和cyclin D3的表达，但不影响NF-κB和i -κB -α的表达。GA处理不抑制AKT信号通路的激活，但诱导组蛋白H3在赖氨酸9和赖氨酸27位点的去乙酰化。下调的SRC-3与更多的HDAC1相互作用介导H3的去乙酰化。Cullin3作为E3连接酶的组成部分，被上调并介导SRC-3的降解。我们的研究结果表明，GA是一种有效的抗肿瘤药物，可用于治疗b细胞NHL，特别是对那些富含SRC-3的人。
Gambogic acid (GA), the active ingredient from gamboges, has been verified as a potent anti-tumor agent in many cancer cells. Nevertheless, its function in lymphoma, especially in B-cell Non-Hodgkin lymphoma (NHL), remains unclear. Amplification and/or overexpression of steroid receptor coactivator-3 (SRC-3) have been detected in multiple tumors and have confirmed its critical roles in carcinogenesis, progression, metastasis and therapy resistance in these cancers. However, no clinical data have revealed the overexpression of SRC-3 and its role in B-cell NHL. In this study, we demonstrated the anti-tumor effects of GA, which included cell growth inhibition, G1/S phase cell cycle arrest and apoptosis in B-cell NHL. We also verified that SRC-3 was overexpressed in B-cell NHL in both cell lines and lymph node samples from patients. The overexpressed SRC-3 was a central drug target of GA, and its down-regulation subsequently modulated down-stream gene expression, ultimately contributing to apoptosis. Silencing SRC-3 decreased the expression of Bcl-2, Bcl-6 and cyclin D3, but not of NF-κB and IκB-α. GA treatment did not inhibit the activation of AKT signaling pathway, but induced the deacetylation of histone H3 at lysine 9 and lysine 27. Down-regulated SRC-3 was observed to interact with more HDAC1 to mediate the deacetylation of H3. As the component of E3 ligase, Cullin3 was up-regulated and mediated the degradation of SRC-3. Our results demonstrate that GA is a potent anti-tumor agent that can be used for therapy against B-cell NHL, especially against those with an abundance of SRC-3.