Elevated SP-1 Transcription Factor Expression and Activity Drives Basal and Hypoxia-induced Vascular Endothelial Growth Factor (VEGF) Expression in Non-Small Cell Lung Cancer

Deacon, Karl; Onion, David; Kumari, Rajendra; Watson, Susan A.; Knox, Alan J.

doi:10.1074/jbc.m112.397042

Cited by 43 publications

(27 citation statements)

References 50 publications

(43 reference statements)

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“…The differential responses at DNA regulation elements despite a common stimulus may account for the tissue-specific regulation of GR expression in different organs. Sp1 is a ubiquitous transcription factor that plays an active role in hypoxia-driven gene expression [38-40]. Sp1 binding sites have been identified at the GR promoter and have been demonstrated to regulate GR expression [22, 36, 41].…”

Section: Discussionmentioning

confidence: 99%

Antenatal hypoxia induces epigenetic repression of glucocorticoid receptor and promotes ischemic-sensitive phenotype in the developing heart

Xiong

Lin

Song

et al. 2016

Journal of Molecular and Cellular Cardiology

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Large studies in humans and animals have demonstrated a clear association of an adverse intrauterine environment with an increased risk of cardiovascular disease later in life. Yet mechanisms remain largely elusive. The present study tested the hypothesis that gestational hypoxia leads to promoter hypermethylation and epigenetic repression of the glucocorticoid receptor (GR) gene in the developing heart, resulting in increased heart susceptibility to ischemia and reperfusion injury in offspring. Hypoxic treatment of pregnant rats from day 15 to 21 of gestation resulted in a significant decrease of GR exon 14, 15, 16, and 17 transcripts, leading to down-regulation of GR mRNA and protein in the fetal heart. Functional cAMP-response elements (CREs) at −4408 and −3896 and Sp1 binding sites at −3425 and −3034 were identified at GR untranslated exon 1 promoters. Hypoxia significantly increased CpG methylation at the CREs and Sp1 binding sites and decreased transcription factor binding to GR exon 1 promoter, accounting for the repression of the GR gene in the developing heart. Of importance, treatment of newborn pups with 5-aza-2’-deoxycytidine reversed hypoxia-induced promoter methylation, restored GR expression and prevented hypoxia-mediated increase in ischemia and reperfusion injury of the heart in offspring. The findings demonstrate a novel mechanism of epigenetic repression of the GR gene in fetal stress-mediated programming of ischemic-sensitive phenotype in the heart.

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Section: Discussionmentioning

confidence: 99%

Antenatal hypoxia induces epigenetic repression of glucocorticoid receptor and promotes ischemic-sensitive phenotype in the developing heart

Xiong

Lin

Song

et al. 2016

Journal of Molecular and Cellular Cardiology

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“…Thus, VEGF, the major factor in the Warburg effect, plays a central role in response to hypoxia. 32 Jackson et al 33 believe that VEGF is the key downstream target of the HIF pathway and plays an important role in the initiation and progression of NSCLC. Zhang et al 34 reported that E6 and E7 upregulated the expression of VEGF at both protein and mRNA levels mediated by HIF-1α in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells

et al. 2017

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Long-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi-directional genetic manipulation and four well-established lung cancer cell lines, we showed HPV16 E6/E7 downregulated expression of liver kinase B1 at both protein and messenger RNA levels; liver kinase B1 downregulated hypoxia-inducible factor 2α at protein level but not at messenger RNA level, and hypoxia-inducible factor 2α upregulated vascular endothelial growth factor at both protein and messenger RNA levels. This is the first study to show hypoxiainducible factor 2α as a downstream effector of liver kinase B1 in lung cancer cells. Our results indicate that HPV16 E6/ E7 indirectly upregulated the expression of vascular endothelial growth factor by inhibition of liver kinase B1 expression and upregulation of hypoxia-inducible factor 2α expression, thus propose a human papillomavirus-liver kinase B1-hypoxia-inducible factor 2α-vascular endothelial growth factor axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of liver kinase B1 in the pathogenesis of human papillomavirus-related lung cancer and suggests novel therapeutic targets. KeywordsHPV16 E6/E7, liver kinase B1, hypoxia-inducible factor 2α, vascular endothelial growth factor, lung cancer Date

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“…Enhanced Sp1 transcription drives basal and hypoxia-induced VEGF expression in non-small cell lung cancer (Colon, et al, 2011;Deacon, et al, 2012), while highly increased Sp1 levels are required for lung tumor growth in transgenic mice bearing Kras-induced lung tumors (Hsu, et al, 2012). Sp1 up-regulates the expression of CD147, a negative prognostic factor that plays an important role in the invasion and metastasis of human lung cancer.…”

Section: Sp Transcription Factors In Lung Cancermentioning

confidence: 99%