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Citrullination modulation stabilizes HIF-1α to promote tumour progression.

ABSTRACT: Citrullination plays an essential role in various physiological or pathological processes, however, whether citrullination is involved in regulating tumour progression and the potential therapeutic significance have not been well explored. Here, we find that peptidyl arginine deiminase 4 (PADI4) directly interacts with and citrullinates hypoxia-inducible factor 1α (HIF-1α) at R698, promoting HIF-1α stabilization. Mechanistically, PADI4-mediated HIF-1α^R698 citrullination blocks von Hippel-Lindau (VHL) binding, thereby antagonizing HIF-1α ubiquitination and subsequent proteasome degradation. We also show that citrullinated HIF-1α^R698, HIF-1α and PADI4 are highly expressed in hepatocellular carcinoma (HCC) tumour tissues, suggesting a potential correlation between PADI4-mediated HIF-1α^R698 citrullination and cancer development. Furthermore, we identify that dihydroergotamine mesylate (DHE) acts as an antagonist of PADI4, which ultimately suppresses tumour progression. Collectively, our results reveal citrullination as a posttranslational modification related to HIF-1α stability, and suggest that targeting PADI4-mediated HIF-1α citrullination is a promising therapeutic strategy for cancers with aberrant HIF-1α expression.

SUBMITTER: Chen R

PROVIDER: S-EPMC11372217 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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Citrullination modulation stabilizes HIF-1α to promote tumour progression.

Chen Rui R Lin Zhiyuan Z Shen Shengqi S Zhu Chuxu C Yan Kai K Suo Caixia C Liu Rui R Wei Haoran H Gao Li L Fan Kaixiang K Zhang Huafeng H Sun Linchong L Gao Ping P

Nature communications 20240903 1

Citrullination plays an essential role in various physiological or pathological processes, however, whether citrullination is involved in regulating tumour progression and the potential therapeutic significance have not been well explored. Here, we find that peptidyl arginine deiminase 4 (PADI4) directly interacts with and citrullinates hypoxia-inducible factor 1α (HIF-1α) at R698, promoting HIF-1α stabilization. Mechanistically, PADI4-mediated HIF-1α<sup>R698</sup> citrullination blocks von Hip ...[more]

PMID: 39227578

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Project description:Background: The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results: The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.

Project description:Hypoxia, a condition characterized by low oxygen levels, serves an important role in the progression of hepatocellular carcinoma (HCC). However, the precise molecular mechanisms underlying hypoxia‑induced HCC progression are yet to be fully elucidated. The present study assessed the involvement of two key factors, hypoxia‑inducible factor‑1α (HIF‑1α) and Rac GTPase activating protein 1 (RACGAP1), in HCC development under hypoxic conditions. HIF‑1α and RACGAP1 genes were overexpressed and knocked down in Hep3B and Huh7 cells using lentiviral transduction and the levels of HIF‑1α and RACGAP1 in the cells were assessed using quantitative PCR, western blotting and immunofluorescence. Co‑immunoprecipitation experiments were performed to evaluate the interaction between HIF‑1α and RACGAP1. Subsequently, the proliferation, apoptosis, migration and invasion of Hep3B and Huh7 cells were assessed using the Cell Counting Kit‑8 assay, flow cytometry, Transwell assay and migration experiments. The expression levels of HIF‑1α and RACGAP1 in normal and HCC tumor samples were analyzed utilizing the Gene Expression Profiling Interactive Analysis database. Furthermore, correlations between HIF‑1α/RACGAP1 gene expression levels and patient survival outcomes were evaluated using the Kaplan‑Meier plotter. Knockdown of HIF‑1α resulted in a significant decrease in RACGAP1 expression, whilst overexpression of HIF‑1α resulted in a significant increase in RACGAP1 expression. Moreover, overexpression and knockdown of RACGAP1 had the same effect on HIF‑1α expression. Additionally, it was demonstrated that HIF‑1α and RACGAP1 interacted directly within a complex. Overexpression of HIF‑1α or RACGAP1 significantly increased proliferation, invasion and migration, and significantly decreased the proportion of apoptotic Hep3B and Huh7 cells. Conversely, knockdown of HIF‑1α or RACGAP1 significantly decreased proliferation, invasion and migration, and significantly increased the proportion of apoptotic Hep3B and Huh7 cells. In addition, the combined knockdown or overexpression of HIF‑1α and RACGAP1 had a more pronounced effect on HCC cell migration compared with knockdown of HIF‑1α alone. Furthermore, there was a significant positive correlation between the expression levels of HIF‑1α and RACGAP1 in HCC tissues and patients with HCC and upregulation of both HIF‑1α and RACGAP1 demonstrated a lower overall survival probability. In conclusion, HIF‑1α and RACGAP1 may synergistically contribute to the development of HCC, highlighting their potential as valuable targets for HCC therapy.

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Citrullination modulation stabilizes HIF-1α to promote tumour progression.

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Citrullination modulation stabilizes HIF-1α to promote tumour progression.

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