RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA
RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA
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RNA 结合蛋白 DAZAP1 通过与 SLC7A11 mRNA 相互作用促进 HCC 进展并调节铁死亡。
DOI：
10.1016/j.yexcr.2020.112453
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发表时间：
2021-02-01
影响因子：
3.7
通讯作者：
Liu, Zhiqian
中科院分区：
文献类型：
--
作者：
Wang, Qi;Guo, Yaxun;Liu, Zhiqian
RNA结合蛋白(RBPs)密切调控着大多数RNA分子的整个生命周期，从转录的早期到RNA的衰变。限制性商业惯例的失调显著影响癌症相关转录本的命运。因此，充分了解恶性疾病中复杂的RBP-RNA调控网络，探索新的治疗靶点是当务之急。RBP DAZAP1(在无精子症相关蛋白1中缺失)最初被认为是精子发生中的一种重要蛋白质，但很少在癌症发生的背景下进行研究。本研究揭示了DAZAP1在肝细胞癌中的作用。DAZAP1的相对表达在肝细胞癌中显著上调，并与患者的几个关键恶性特征和术后生存不良呈正相关。小干扰RNA下调DAZAP1基因可显著抑制肝癌细胞的增殖、迁移和侵袭。此外，DAZAP1显著降低了细胞对索拉非尼(SF)的敏感性，索拉非尼通过靶向系统XC(-)(由轻链XCT/SLC7A11和重链4F2重链组成)被证明是铁下垂的诱导剂。在机制水平上，DAZAP1被认为是一种有效的铁下垂抑制因子和SLC7A11mRNA的有效结合伙伴。进一步的研究表明，DAZAP1与SLC7A11基因的3‘非翻译区相互作用，并正向调节其稳定性。在我们的工作中，我们阐明了DAZAP1的新功能，并初步揭示了其在铁性下垂中的潜在机制，这可能有助于探索肝癌患者的生物标志物和治疗靶点。
RNA-binding proteins (RBPs) closely regulate the whole lifecycle of most RNA molecules, from the very early stage of transcription to RNA decay. Dysregulation of RBPs significantly affects the fate of cancer-related transcripts. Therefore, it is imperative to fully understand the complicated RBP-RNA regulatory networks in malignant diseases and to explore novel therapeutic targets. The RBP DAZAP1 (deleted in azoospermia-associated protein 1), originally identified as an important protein in spermatogenesis, had rarely been studied in the context of carcinogenesis. The role of DAZAP1 in hepatocellular carcinoma (HCC) was unveiled in this study. The relative expression of DAZAP1 was significantly upregulated in HCC and was positively associated with several key malignant characteristics and poor postoperative survival in patients. DAZAP1 knockdown by small interfering RNA markedly inhibited HCC cell proliferation, migration and invasion. Furthermore, DAZAP1 significantly reduced cellular sensitivity to sorafenib (SF), which had been proven to be an inducer of ferroptosis by targeting the system Xc(-) (composed of a light chain, xCT/SLC7A11, and a heavy chain, 4F2 heavy chain). At the mechanistic level, DAZAP1 was identified as a potent inhibitor of ferroptosis and an efficient binding partner of SLC7A11 mRNA. Further study revealed that DAZAP1 interacted with the 3'UTR (untranslated region) of SLC7A11 mRNA and positively regulated its stability. In our work, we clarified novel functions of DAZAP1 and preliminarily revealed its underlying mechanism in ferroptosis, which may be conducive to the exploration of biomarkers and therapeutic targets in HCC patients.