AEG-1 regulates retinoid X receptor and inhibits retinoid signaling.
AEG-1 regulates retinoid X receptor and inhibits retinoid signaling.
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DOI：
10.1158/0008-5472.can-14-0421
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发表时间：
2014-08-15
期刊：
影响因子：
11.2
通讯作者：
Sarkar D
中科院分区：
文献类型：
--
作者：
Srivastava J;Robertson CL;Rajasekaran D;Gredler R;Siddiq A;Emdad L;Mukhopadhyay ND;Ghosh S;Hylemon PB;Gil G;Shah K;Bhere D;Subler MA;Windle JJ;Fisher PB;Sarkar D
维甲酸X受体（RXR）调节关键的细胞反应，如细胞生长和发育，这种调节在各种恶性肿瘤中经常受到干扰，包括肝细胞癌（HCC）。然而，在物理上控制这种失调的分子大多是未知的。在这里，我们将RXR鉴定为星形胶质细胞升高基因-1（AEG-1）/Metadherin（MTDH）的相互作用伴侣，MTDH是一种在所有癌症中上调的癌基因。在相互作用后，AEG-1深刻地抑制RXR/视黄酸受体（RAR）介导的转录激活。因此，AEG-1显着保护HCC和急性髓性白血病（AML）细胞从类维生素A和类rexinoid诱导的细胞死亡。在非致瘤性细胞和原代肝细胞中，AEG-1/RXR共定位于细胞核中，其中AEG-1干扰转录共激活因子向RXR的募集，从而阻止靶基因的转录。在肿瘤细胞和AEG-1转基因肝细胞中，过表达的AEG-1将RXR捕获在细胞质中，阻止其核转位。此外，由AEG-1激活的ERK使RXR磷酸化，这导致其功能失活和配体依赖性反式激活的减弱。在裸鼠模型中，全反式维甲酸（ATRA）和AEG-1敲低的组合协同抑制人HCC异种移植物的生长。本研究确定AEG-1作为一种新的RXR和RXR/RAR的稳态调节剂，可能有助于肝癌的发生。靶向AEG-1可以使HCC和AML患者对基于维甲酸和类维生素A的治疗方法敏感。
Retinoid X Receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including Hepatocellular Carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of Astrocyte Elevated Gene-1 (AEG-1)/Metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/Retinoic Acid Receptor (RAR)-mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myeloid leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In non-tumorigenic cells and primary hepatocytes, AEG-1/RXR co-localizes in the nucleus where AEG-1 interferes with recruitment of transcriptional co-activators to RXR preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. Additionally, ERK, activated by AEG-1, phosphorylates RXR which leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize HCC and AML patients to retinoid- and rexinoid-based therapeutics.