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RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA.
- Source :
-
Experimental cell research [Exp Cell Res] 2021 Feb 01; Vol. 399 (1), pp. 112453. Date of Electronic Publication: 2020 Dec 29. - Publication Year :
- 2021
-
Abstract
- 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 <superscript>-</superscript> (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.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Transport System y+ genetics
Animals
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular metabolism
Cell Line, Tumor
Disease Progression
Hep G2 Cells
Humans
Liver Neoplasms genetics
Liver Neoplasms metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Metastasis
Protein Binding
RNA, Messenger metabolism
RNA-Binding Proteins metabolism
Amino Acid Transport System y+ metabolism
Carcinoma, Hepatocellular pathology
Ferroptosis genetics
Liver Neoplasms pathology
RNA-Binding Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2422
- Volume :
- 399
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Experimental cell research
- Publication Type :
- Academic Journal
- Accession number :
- 33358859
- Full Text :
- https://doi.org/10.1016/j.yexcr.2020.112453