Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy

Xu, Dazhong

doi:10.3389/fcell.2021.646687

Cited by 12 publications

(15 citation statements)

References 154 publications

(329 reference statements)

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“…Two SIAH homologs in humans (SIAH1 and Siah2) and three homologs in mice (Siah1a, Siah1b, and Siah2) have been reported (18). SIAH proteins contain an N-terminal RING domain and a C-terminal substrate-binding domain (SBD) (19), which are involved in ubiquitination of diverse substrates and other biological processes such as RAS signaling, DNA damage, hypoxia, p38/JNK/NF-кB pathways, and transcription (20)(21)(22). In particular, Siah2 plays a critical role in tumorigenesis and cancer progression (23).…”

Section: Introductionmentioning

confidence: 99%

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

Zheng

Wang

et al. 2022

Front. Immunol.

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N6-methyladenosine (m6A) has been reported as an important mechanism of post-transcriptional regulation. Programmed death ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. In addition, seven in absentia homolog 2 (Siah2), a RING E3 ubiquitin ligase, has been involved in tumorigenesis and cancer progression. However, the role of m6A-METTL14-Siah2-PD-L1 axis in immunotherapy remains to be elucidated. In this study, we showed that METTL14, a component of the m6A methyltransferase complex, induced Siah2 expression in cholangiocarcinoma (CCA). METTL14 was shown to enrich m6A modifications in the 3’UTR region of the Siah2 mRNA, thereby promoting its degradation in an YTHDF2-dependent manner. Furthermore, co-immunoprecipitation experiments demonstrated that Siah2 interacted with PD-L1 by promoting its K63-linked ubiquitination. We also observed that in vitro and in vivo Siah2 knockdown inhibited T cells expansion and cytotoxicity by sustaining tumor cell PD-L1 expression. The METTL14-Siah2-PD-L1–regulating axis was further confirmed in human CCA specimens. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with low Siah2 levels were more sensitive to anti-PD1 immunotherapy. Taken together, our results evidenced a new regulatory mechanism of Siah2 by METTL14-induced mRNA epigenetic modification and the potential role of Siah2 in cancer immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

Zheng

Wang

et al. 2022

Front. Immunol.

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“…The level of HIF-1α is largely regulated oxygen dependently by the ubiquitin/proteasome-mediated process ( Xu and Li, 2021 ). To further verify whether UDCA promoted HIF-1α degradation through the ubiquitin–proteasome pathway, the proteasome inhibitor MG132 was applied.…”

Section: Resultsmentioning

confidence: 99%

UDCA Inhibits Hypoxic Hepatocellular Carcinoma Cell–Induced Angiogenesis Through Suppressing HIF-1α/VEGF/IL-8 Intercellular Signaling

Lin

Huang

et al. 2021

Front. Pharmacol.

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Background: A hypoxic microenvironment may induce angiogenesis and promote the development of hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether ursodeoxycholic acid (UDCA) may inhibit hypoxic HCC cell–induced angiogenesis and the possible mechanisms.Methods: Tube formation and matrigel plug angiogenesis assays were used to evaluate angiogenesis in vitro and in vivo, respectively. Real-time PCR, enzyme-linked immunosorbent assay, and Western blot were used to evaluate the mRNA and protein expressions of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and IL-8, respectively. Dual-luciferase reporter assay was applied to assess the reporter gene expression of hypoxia-response element (HRE).Results: UDCA antagonized hypoxic Huh 7 cell-induced tube formation of EA.hy 926 cells. In HCC cells, UDCA inhibited hypoxia-induced upregulation of VEGF and IL-8 both in mRNA and protein levels. UDCA also inhibited IL-8–induced angiogenesis in vitro and in vivo through suppressing IL-8–induced phosphorylation of ERK. The levels of HIF-1α mRNA and protein and HRE-driven luciferase activity in HCC cells were upregulated by hypoxia and were all inhibited by UDCA. The proteasome inhibitor MG132 antagonized the effect of UDCA on HIF-1α degradation. In hypoxic condition, the phosphorylation of ERK and AKT was obviously increased in HCC cells, which was suppressed by UDCA. Transfection of the HIF-1α overexpression plasmid reversed the effects of UDCA on hypoxic HCC cell–induced angiogenesis, HRE activity, and expressions of IL-8 and VEGF.Conclusions: Our results demonstrated that UDCA could inhibit hypoxic HCC cell–induced angiogenesis through suppressing HIF-1α/VEGF/IL-8–mediated intercellular signaling between HCC cells and endothelial cells.

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“…Interestingly, crucial proteins modulating stem cell self-renewal and differentiation such as HIF-1a, FoxOs, APE1/Ref-1, Nrf2, ATM, p38, and p53 have been identified as redox-sensitive proteins. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor and a master regulator of the cellular response to hypoxia [ 22 ]. HIF-1 is involved in the maintenance of both cell-cycle quiescence and stem cell state, playing a key role in preserving the stem cell pool [ 23 , 24 ].…”

Section: Noxs and Ros: Effectors And Modulators Of Redox And Metabolic Homeostasis In Stem Cellsmentioning

confidence: 99%

NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function

et al. 2021

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One of the major sources of reactive oxygen species (ROS) generated within stem cells is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOXs), which are critical determinants of the redox state beside antioxidant defense mechanisms. This balance is involved in another one that regulates stem cell fate: indeed, self-renewal, proliferation, and differentiation are decisive steps for stem cells during embryo development, adult tissue renovation, and cell therapy application. Ex vivo culture-expanded stem cells are being investigated for tissue repair and immune modulation, but events such as aging, senescence, and oxidative stress reduce their ex vivo proliferation, which is crucial for their clinical applications. Here, we review the role of NOX-derived ROS in stem cell biology and functions, focusing on positive and negative effects triggered by the activity of different NOX isoforms. We report recent findings on downstream molecular targets of NOX-ROS signaling that can modulate stem cell homeostasis and lineage commitment and discuss the implications in ex vivo expansion and in vivo engraftment, function, and longevity. This review highlights the role of NOX as a pivotal regulator of several stem cell populations, and we conclude that these aspects have important implications in the clinical utility of stem cells, but further studies on the effects of pharmacological modulation of NOX in human stem cells are imperative.

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Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy

Cited by 12 publications

References 154 publications

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

UDCA Inhibits Hypoxic Hepatocellular Carcinoma Cell–Induced Angiogenesis Through Suppressing HIF-1α/VEGF/IL-8 Intercellular Signaling

NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function

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