Targeting HIF-2α as therapy for advanced cancers

Murugesan, Thanabal; Rajajeyabalachandran, Gurukumari; Kumar, Swetha; Nagaraju, Shruthi; Jegatheesan, Sooriya Kumar

doi:10.1016/j.drudis.2018.05.003

Cited by 33 publications

(27 citation statements)

References 80 publications

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“…Growing evidence have revealed that HIF-1α and HIF-2α inhibitors block tumor growth through a variety of mechanisms [ 18 , 300 ]. HIF-1α inhibitors have the most types, among which HDAC inhibitors are indirectly involved in epigenetic regulation [ 136 , 301 ].…”

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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“…However, their role in tumorigenesis remains controversial as both have been described as both oncogenes and tumors suppressors in a tumor context dependent manner. HIF1α has been suggested to be involved in the early stages of cancer while HIF2α in the late stages and chronic rather than acute hypoxia [121]. High expression of HIF1α in biopsies of brain, breast, cervical, esophageal, oropharyngeal and ovarian cancers is correlated with treatment failure, mortality and promotes tumor progression [122].…”

Section: Hif2αmentioning

confidence: 99%

EPAS1/HIF2α correlates with features of low-risk neuroblastoma and with adrenal chromaffin cell differentiation during sympathoadrenal development

Westerlund

Shi

Holmberg

2019

Biochemical and Biophysical Research Communications

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“…Ferrous ion (Fe 2+ ) is essential for regulating enzymatic activity in DNA synthesis, DNA repair and epigenetic regulation, as well as the control of cell proliferation; however it also enhances tumor growth [ 30 ]. Fe 2+ is incorporated into PHD as a co-factor to hydroxylate HIF-α, and this iron controls the HIF and WNT signaling pathways in cancer [ 31 , 32 , 33 ]. In this study, the PHDs expression increased after CP knockdown.…”

Section: Discussionmentioning

confidence: 99%

“…The CP affected both Fe 2+ and PHDs amount. HIF-2α has been previously reported to be linked with various disease processes in cancer development, including tumorigenesis, proliferation, metastasis, tumor angiogenesis and chemoresistance [ 33 , 34 , 35 ]. Enhancement of HIF-2α has been linked to cancers in brain, head/neck, melanoma, lung and confers poor prognosis [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis

Tsai

Chang

et al. 2020

IJMS

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For decades, lung cancer has been the leading cause of cancer-related death worldwide. Hypoxia-inducible factors (HIFs) play critical roles in mediating lung cancer development and metastasis. The present study aims to clarify how HIF’s over-activation affects lung cancer angiogenesis not only in a normoxic condition, but also a hypoxic niche. Our study shows that human lung cancer exhibits elevated levels of ceruloplasmin (CP), which has a negative impact on the prognosis of patients. CP affects the cellular Fe2+ level, which inactivates prolyl hydroxylase (PHD) 1 and 2, resulting in HIF-2α enhancement. Increased HIF-2α leads to vascular endothelial growth factor-A (VEGF-A) secretion and angiogenesis. The expression of CP is under the epigenetic control of miR-145-5p. Restoration of miR-145-5p by miRNA mimics transfection decreases CP expression, increases Fe2+ and PHD1/2 levels and HIF hydroxylation while reduced HIF-2α levels resulting in the inhibition of tumor angiogenesis. In contrast, inhibition of miR-145-5p by miRNA inhibitors increases the expression of CP and VEGF-A in lung cancer cells. Significantly, miR-145-5p expression is lost in the tumor samples of lung cancer patients, and low miR-145-5p expression is strongly correlated with a shorter overall survival time. In conclusion, the current study reveals the clinical importance and prognostic value of miR-145-5p and CP. It identifies a unique mechanism of HIF-2α over-activation, which is mediated by iron imbalance of the iron-PHD coupling that modulates tumor angiogenesis.

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Targeting HIF-2α as therapy for advanced cancers

Cited by 33 publications

References 80 publications

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

EPAS1/HIF2α correlates with features of low-risk neuroblastoma and with adrenal chromaffin cell differentiation during sympathoadrenal development

Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis

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