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MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma.

ABSTRACT: Hypoxia is an important tumor feature and hypoxia-inducible factor 1 (HIF-1) is a master regulator of cell response to hypoxia. Mouse double minute 2 homolog (MDM2) promotes cancer cell survival in retinoblastoma (RB), with the underlying mechanism remaining elusive. In this study, we investigated the role of MDM2 and its relation to HIF-1α in RB. Expression analysis on primary human RB samples showed that MDM2 expression was positively correlated with that of HIF-1α while negatively correlated with von Hippel-Lindau protein (pVHL), the regulator of HIF-1α. In agreement, RB cells with MDM2 overexpression showed increased expression of HIF-1α and decreased expression of pVHL, while cells with MDM2 siRNA knockdown or MDM2-specific inhibitor showed the opposite effect under hypoxia. Further immuno-precipitation analysis revealed that MDM2 could directly interact with pVHL and promotes its ubiquitination and degradation, which consequently led to the increase of HIF-1α. Inhibition of MDM2 and/or HIF-1α with specific inhibitors induced RB cell death and decreased the stem cell properties of primary RB cells. Taken together, our study has shown that MDM2 promotes RB survival through regulating the expression of pVHL and HIF-1α, and targeting MDM2 and/or HIF-1α represents a potential effective approach for RB treatment.

SUBMITTER: Zhang S

PROVIDER: S-EPMC9892057 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma.

Zhang Shouhua S Xu Hongyan H Li Weiming W Ji Jianfeng J Jin Qifang Q Chen Leifeng L Gan Qiang Q Tao Qiang Q Chai Yong Y

Pathology oncology research : POR 20230119

Hypoxia is an important tumor feature and hypoxia-inducible factor 1 (HIF-1) is a master regulator of cell response to hypoxia. Mouse double minute 2 homolog (MDM2) promotes cancer cell survival in retinoblastoma (RB), with the underlying mechanism remaining elusive. In this study, we investigated the role of MDM2 and its relation to HIF-1α in RB. Expression analysis on primary human RB samples showed that MDM2 expression was positively correlated with that of HIF-1α while negatively correlated ...[more]

PMID: 36741966

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Project description:BackgroundProtein/nucleic acid deglycase (DJ-1) and hypoxia-inducible factor-1α (HIF-1α) play significant roles in the progression of various types of cancer and are associated with the phosphatidylinositol 3-kinase (PI3K) pathway. However, their functions in colorectal cancer (CRC) have not been identified. The aim of this study was to analyze the putative signaling pathway encompassing DJ-1, PI3K, and HIF-1α in a series of CRC tissues and cell lines.PurposeThis study aimed at exploring the expression status of DJ-1 in colon cancer and its role in survival of cancer cell lines.MethodsThe expression and localization of DJ-1, PI3K-p110α, phosphorylated Akt (p-AKT), and HIF-1α were determined by immunohistochemistry in 73 resected CRC tissues. The effect of DJ-1 on cell activity was explored by in vitro knockdown and overexpression experiments in SW480 and HT-29 cells. The cells were treated with a PI3K inhibitor (LY294002 or wortmannin), and p-AKT and HIF-1α protein expression were then analyzed. Apoptosis was analyzed by flow cytometry. The expression levels of several HIF-1 target genes were assessed under hypoxic conditions by reverse transcription-PCR and Western blot. Xenograft tumor growth studies were conducted in DJ-1 knockdown or overexpression cells.ResultsHigh DJ-1 expression was found in 68.49% (50/73) of CRC tissues and associated with larger tumor size and advanced clinical stages. DJ-1 expression was positively associated with PI3K-p110α, p-AKT, and HIF-1α expression in CRC. HIF-1α and p-AKT protein levels were lower in SW480 and HT-29 cells with stable DJ-1 knockdown than in those with DJ-1 overexpression. PI3K inhibitors almost completely blocked DJ-1-induced AKT phosphorylation. However, the expression of HIF-1α was partially preserved after treatment with PI3K inhibitors. We also show that DJ-1 is necessary for the transcriptional ability of HIF-1α and CRC cell survival after hypoxic stress. Moreover, DJ-1 promoted the growth of established tumor xenografts in nude mice.ConclusionOur findings are the first to show that DJ-1 is overexpressed in CRC. We suggest a model in which DJ-1 mediates CRC cell survival by regulating the PI3K-AKT-HIF-1α pathway.

Dataset Information

MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma.

Publications

MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma.

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