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FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma

The hypoxic microenvironment is an important contributor of glioblastoma (GBM) aggressiveness via HIF1α, while tumour inflammation is profoundly influenced by FAT Atypical Cadherin (FAT1). This study was designed to explore the functional interaction and significance of FAT1 and HIF1α under severe h...

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Autores principales: Madan, Evanka, Dikshit, Bhawana, Gowda, Srinivas H., Srivastava, Chitrangda, Sarkar, Chitra, Chattopadhyay, Parthaprasad, Sinha, Subrata, Chosdol, Kunzang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585695/
https://www.ncbi.nlm.nih.gov/pubmed/27536856
http://dx.doi.org/10.1002/ijc.30386
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author Madan, Evanka
Dikshit, Bhawana
Gowda, Srinivas H.
Srivastava, Chitrangda
Sarkar, Chitra
Chattopadhyay, Parthaprasad
Sinha, Subrata
Chosdol, Kunzang
author_facet Madan, Evanka
Dikshit, Bhawana
Gowda, Srinivas H.
Srivastava, Chitrangda
Sarkar, Chitra
Chattopadhyay, Parthaprasad
Sinha, Subrata
Chosdol, Kunzang
author_sort Madan, Evanka
collection PubMed
description The hypoxic microenvironment is an important contributor of glioblastoma (GBM) aggressiveness via HIF1α, while tumour inflammation is profoundly influenced by FAT Atypical Cadherin (FAT1). This study was designed to explore the functional interaction and significance of FAT1 and HIF1α under severe hypoxia‐mimicking tumour microenvironment in primary human tumours. We first identified a positive correlation of FAT1 with HIF1α and its target genes in GBM tumour specimens, revealing the significance of the FAT1‐HIF1α axis in glioma cells. We found that severe hypoxia leads to an increased expression of FAT1 and HIF1α in U87MG and U373MG cells. To reveal the relevance of FAT1 under hypoxic conditions, we depleted endogenous FAT1 under hypoxia and found a substantial reduction in the expression of HIF1α and its downstream target genes like CA9, GLUT1, VEGFA, MCT4, HK2, BNIP3 and REDD1, as well as a significant reduction in the invasiveness in GBM cells. At the molecular level, under hypoxia the FAT1 depletion‐associated reduction in HIF1α was due to compromised EGFR‐Akt signaling as well as increased VHL‐dependent proteasomal degradation of HIF1α. In brief, for the first time, these results reveal an upstream master regulatory role of FAT1 in the expression and role of HIF1α under hypoxic conditions and that FAT1‐HIF1α axis controls the invasiveness of GBM. Hence, FAT1 represents a novel potential therapeutic target for GBM.
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spelling pubmed-65856952019-06-27 FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma Madan, Evanka Dikshit, Bhawana Gowda, Srinivas H. Srivastava, Chitrangda Sarkar, Chitra Chattopadhyay, Parthaprasad Sinha, Subrata Chosdol, Kunzang Int J Cancer Molecular Cancer Biology The hypoxic microenvironment is an important contributor of glioblastoma (GBM) aggressiveness via HIF1α, while tumour inflammation is profoundly influenced by FAT Atypical Cadherin (FAT1). This study was designed to explore the functional interaction and significance of FAT1 and HIF1α under severe hypoxia‐mimicking tumour microenvironment in primary human tumours. We first identified a positive correlation of FAT1 with HIF1α and its target genes in GBM tumour specimens, revealing the significance of the FAT1‐HIF1α axis in glioma cells. We found that severe hypoxia leads to an increased expression of FAT1 and HIF1α in U87MG and U373MG cells. To reveal the relevance of FAT1 under hypoxic conditions, we depleted endogenous FAT1 under hypoxia and found a substantial reduction in the expression of HIF1α and its downstream target genes like CA9, GLUT1, VEGFA, MCT4, HK2, BNIP3 and REDD1, as well as a significant reduction in the invasiveness in GBM cells. At the molecular level, under hypoxia the FAT1 depletion‐associated reduction in HIF1α was due to compromised EGFR‐Akt signaling as well as increased VHL‐dependent proteasomal degradation of HIF1α. In brief, for the first time, these results reveal an upstream master regulatory role of FAT1 in the expression and role of HIF1α under hypoxic conditions and that FAT1‐HIF1α axis controls the invasiveness of GBM. Hence, FAT1 represents a novel potential therapeutic target for GBM. John Wiley and Sons Inc. 2016-08-29 2016-12-01 /pmc/articles/PMC6585695/ /pubmed/27536856 http://dx.doi.org/10.1002/ijc.30386 Text en © 2016 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Molecular Cancer Biology
Madan, Evanka
Dikshit, Bhawana
Gowda, Srinivas H.
Srivastava, Chitrangda
Sarkar, Chitra
Chattopadhyay, Parthaprasad
Sinha, Subrata
Chosdol, Kunzang
FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma
title FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma
title_full FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma
title_fullStr FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma
title_full_unstemmed FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma
title_short FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma
title_sort fat1 is a novel upstream regulator of hif1α and invasion of high grade glioma
topic Molecular Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585695/
https://www.ncbi.nlm.nih.gov/pubmed/27536856
http://dx.doi.org/10.1002/ijc.30386
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