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Review
. 2022 Sep 8;11(18):2811.
doi: 10.3390/cells11182811.

Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy

Minghui Zhang  1 , Yu Zhang  1 , Yubo Ding  2 , Jialu Huang  1 , Jingwei Yao  2 , Zhuoyi Xie  1 , Yufan Lv  2 , Jianhong Zuo  1   2   3
Affiliations
Review

Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy

Minghui Zhang et al. Cells. .

Abstract

Previous studies have shown that tumors under a hypoxic environment can induce an important hypoxia-responsive element, hypoxia-induced factor-1α (HIF-1α), which can increase tumor migration, invasion, and metastatic ability by promoting epithelial-to-mesenchymal transition (EMT) in tumor cells. Currently, with the deeper knowledge of long noncoding RNAs (lncRNAs), more and more functions of lncRNAs have been discovered. HIF-1α can regulate hypoxia-responsive lncRNAs under hypoxic conditions, and changes in the expression level of lncRNAs can regulate the production of EMT transcription factors and signaling pathway transduction, thus promoting EMT progress. In conclusion, this review summarizes the regulation of the EMT process by HIF-1α and lncRNAs and discusses their relationship with tumorigenesis. Since HIF-1α plays an important role in tumor progression, we also summarize the current drugs that inhibit tumor progression by modulating HIF-1α.

Keywords: EMT; HIF-1α; HIF-1α inhibitors; hypoxia; lncRNAs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure A1
Figure A1
HIF-1 is a heterodimeric complex consisting of an HIF-1α subunit and an HIF-1β subunit. HIF-1α contains multiple functional structural domains, including the bHLH structural domain, the PAS structural domain, the ODD structural domain, and the TAD structural domain. The bHLH and PAS domains are involved in dimerization and DNA binding, while the ODD domain is mainly involved in the proteasomal degradation of HIF-1α under normoxic conditions, and the TAD domain is involved in the regulation of target genes by HIF-1α. Abbreviations: bHLH: basic helix−loop−helix; PAS: Per-ARNT-Sim; TAD: trans-activation structural domain; ODD: oxygen-dependent degradation structural domain.
Figure A2
Figure A2
Under normoxic conditions, translated HIF-1α is recognized by PVHL proteins after the hydroxylation of its proline residues (Pro-402 and Pro-564) by PHD proteins, after which the PVHL protein recruits ubiquitin ligase to bind to HIF-1α, and the HIF-1α bound to ubiquitin ligase enters the proteasome to be crushed and degraded, eventually losing its biological function. Conversely, the hydroxylation of HIF-1α is inhibited under hypoxia; the accumulated HIF-1α enters the nucleus, binds to another partner HIF-1β to form a dimer, and, with the help of coactivators such as CBP/P300, activates VEGF, GLUT1, and other target genes’ transcriptional expression, thereby performing critical biological functions such as promoting hypoxia-induced angiogenesis, cell metabolism, proliferation, invasion, metastasis, etc. Abbreviations: PVHL: von Hippel–Lindau; PHDs: prolyl hydroxylase domain; CBP/P300: cAMP response element-binding, protein-binding protein; HRE: hypoxia response element; VEGF: vascular endothelial cell growth factor; GLUT1: Glucose transporter 1.
Figure A3
Figure A3
EMT is the process of epithelial-to-mesenchymal transition, during which epithelial markers such as E-cadherin and claudins are decreased, while mesenchymal markers such as vimentin, N-cadherin, fibronectin, and MMPs are increased. Hypoxia-induced HIF-1α can regulate the expression level of lncRNA and form a mutual activation pathway with lncRNA, thereby promoting the production of EMT-TFs and promoting the process of tumor EMT.
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Grants and funding

This research was funded by the Key Research Program from the Science and Technology Department of Ningxia Hui Autonomous Region, China (2019BFH02012); the Key Research Program of Hunan Health Committee (20201909); the Program of Hengyang Science and Technology Bureau (2017-1, 2020-67); the National Natural Science Foundation of China (8217114243); The 4310 Program of Hengyang Medical College, University of South China (20224310NHYCG12).

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