Hypoxia Alters the Response to Anti-EGFR Therapy by Regulating EGFR Expression and Downstream Signaling in a DNA Methylation–Specific and HIF-Dependent Manner

Mamo, Mahelet; Ye, I. Chae; DiGiacomo, Josh W.; Park, Je Yeon; Downs, Bradley M.; Gilkes, Daniele M.

doi:10.1158/0008-5472.can-20-1232

Cited by 30 publications

(23 citation statements)

References 50 publications

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“…Most CGIs in gene promoters are unmethylated, allowing active transcription [ 5 ]. CGI methylation changes are hallmarks of many human cancers and lead to concomitant gene inactivation [ 6 – 8 ]. DNA methyltransferase 1 (DNMT1) is a major DNA methyltransferase responsible for methylation maintenance during DNA replication, and inactivation of DNMT1 in mice results in early embryonic lethality [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A

et al. 2021

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Peroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found that PPARA was expressed at relatively low levels in pancancers, and Kaplan-Meier analyses revealed that high PPARA protein expression was correlated with better survival of patients with colon cancer. In vitro experiments showed that fenofibrate regulated cell cycle distribution, promoted apoptosis, and suppressed cell proliferation and epithelial mesenchymal transition by activating PPARA. PPARA activation inhibited DNMT1 activity and abolished methylation-mediated CDKN2A repression. Downregulation of cyclin-CDK complexes led to the restoration of CDKN2A, which caused cell cycle arrest in the G1 phase via regulation of the CDKN2A/RB/E2F pathway. Finally, we demonstrated that fenofibrate administration inhibited tumor growth and DNMT1 activity in vivo. The PPARA agonist, fenofibrate, might serve as an applicable agent for epigenetic therapy of colon cancer patients.

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Section: Introductionmentioning

confidence: 99%

Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A

et al. 2021

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“…Given that hypoxia is associated with increased malignancy, resistance to therapy and distant metastasis in solid tumors, including NPC [ 20 , 21 ], we hypothesized that hypoxia may mediate the up-regulation of miR-182-5p in NPC. To this end, miR-182-5p levels were measured by qPCR in cells cultured in the hypoxic incubator at different time points.…”

Section: Resultsmentioning

confidence: 99%

The oncogenic role of HIF-1α/miR-182-5p/ZFP36L1 signaling pathway in nasopharyngeal carcinoma

Wang

Zhou

et al. 2021

Cancer Cell Int

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Background Accumulating evidence indicates that dysregulation of miR-182-5p can serve as diagnostic and prognostic biomarkers for some cancers, whereas the role of miR-182-5p has not been explored in nasopharyngeal carcinoma (NPC). Our study aims to elucidate the biological function of miR-182-5p in NPC and the potential molecular mechanism involved. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine miR-182-5p expression in NPC primary tissues and cell lines. Immunohistochemistry (IHC) for ZFP36L1 was conducted in NPC samples. Western blot was used to evaluate protein expression in cell lines. A series of functional assays were carried out to evaluate the roles of miR-182-5p and ZFP36L1 in tumor development and progression of NPC. Bioinformatics tools and luciferase reporter assays were utilized to identify the potential mechanisms of action. Moreover, rescue experiments were applied to explore whether ZFP36L1 mediated the effects of miR-182-5p in NPC. Results Up-regulation of miR-182-5p was significantly associated with tumor development and poor prognosis in patients with NPC. Functional study demonstrated that miR-182-5p overexpression enhanced, whereas suppression of miR-182-5p impeded NPC cell proliferation, migration, tumorigenesis and metastasis. Mechanistically, miR-182-5p interacted with ZFP36L1 at two sites in its 3′ un-translated region (UTR) and repressed ZFP36L1 expression in NPC. Consistently, an inverse correlation was observed between the expression levels of miR-182-5p and ZFP36L1 using clinical NPC tissues, and down-regulation of ZFP36L1 in NPC predicts poor survival. Furthermore, overexpression of miR-182-5p in NPC was partly attributable to the transcriptional activation effect induced by hypoxia-inducible factor 1α (HIF-1α). Conclusions Our data suggests that miR-182-5p facilitates cell proliferation and migration in NPC through its ability to down-regulate ZFP36L1 expression, and that the HIF-1α/miR-182-5p/ZFP36L1 axis may serve as a novel therapeutic target in the management of NPC.

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“…V-ATPase and EGFR can antagonize one another [ 32 ]. The induction of EGFR under hypoxic conditions has been found to promote cell proliferation and migration, and patients with hypoxic breast tumors and EGFR hypomethylation may benefit from EGFR inhibition [ 33 ]. Unfortunately, the specific mode of interaction between EGFR and ATP6AP1 in BC is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and immunological value of ATP6AP1 in breast cancer: implications for SARS-CoV-2

Wang

Liu

Zhang

2021

Aging

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Abnormal ATPase H+ Transporting Accessory Protein 1 ( ATP6AP1 ) expression may promote carcinogenesis. We investigated the association of ATP6AP1 with breast cancer (BC) and COVID-19. The Oncomine, Gene Expression Profiling Interactive Analysis, Human Protein Atlas and Kaplan-Meier plotter databases were used to evaluate the expression and prognostic value of ATP6AP1 in BC. ATP6AP1 was upregulated in BC tissues, and higher ATP6AP1 expression was associated with poorer outcomes. Data from the Tumor Immune Estimation Resource, Tumor-Immune System Interaction Database and Kaplan-Meier plotter indicated that ATP6AP1 expression correlated with immune infiltration, and that its prognostic effects in BC depended on tumor-infiltrating immune cell subtype levels. Multiple databases were used to evaluate the association of ATP6AP1 with clinicopathological factors, assess the mutation and methylation of ATP6AP1 , and analyze gene co-expression and enrichment. The ATP6AP1 promoter was hypomethylated in BC tissues and differentially methylated between different disease stages and subtypes. Data from the Gene Expression Omnibus indicated that ATP6AP1 levels in certain cell types were reduced after SARS-CoV-2 infections. Ultimately, higher ATP6AP1 expression was associated with a poorer prognosis and with higher or lower infiltration of particular immune cells in BC. BC patients may be particularly susceptible to SARS-CoV-2 infections, which may alter their prognoses.

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Hypoxia Alters the Response to Anti-EGFR Therapy by Regulating EGFR Expression and Downstream Signaling in a DNA Methylation–Specific and HIF-Dependent Manner

Cited by 30 publications

References 50 publications

Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A

Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A

The oncogenic role of HIF-1α/miR-182-5p/ZFP36L1 signaling pathway in nasopharyngeal carcinoma

Prognostic and immunological value of ATP6AP1 in breast cancer: implications for SARS-CoV-2

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