STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells.
Aberrantly enhanced vascular endothelial growth factor (VEGF) gene expression is associated with increased tumor growth and metastatic spread of solid malignancies, including human renal carcinomas. Persistent activation of STAT3 is linked to tumor-associated angiogenesis, but underlying mechanisms remain unclear. Therefore, we examined whether STAT3 modulates the stability and activity of hypoxia-inducible factor-1alpha (HIF-1alpha), and in turn enhances VEGF expression. We found that STAT3 was activated in ischemic rat kidneys and hypoxic human renal carcinoma cells. We also found that hypoxia-induced activation of STAT3 transactivated the VEGF promoter and increased the expression of VEGF transcripts. Consistent with these findings, STAT3 inhibition attenuated the hypoxic induction of VEGF. Interestingly, activated STAT3 increased HIF-1alpha protein levels due to the HIF-1alpha stability by blocking HIF-1alpha degradation and accelerated its de novo synthesis. The novel interaction of STAT3 with HIF-1alpha was identified in hypoxic renal carcinoma cells. Furthermore, hypoxia recruited STAT3, HIF-1alpha, and p300 to the VEGF promoter and induced histone H3 acetylation. Therefore, these findings provide compelling evidence that a causal relationship exists between STAT3 activation and HIF-1-dependent angiogenesis and suggest that therapeutic modalities designed to disrupt STAT3 signaling hold considerable promise for the blocking tumor growth and enhancing apoptosis of cancer cells and tissues.
Jung
Joo Eun
JE
Department of Pharmacology, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea.
Lee
Hyun Gyu
HG
Cho
Ik Hyun
IH
Chung
Doo Hyun
DH
Yoon
Sun-Hee
SH
Yang
Young Mok
YM
Lee
Jung Weon
JW
Choi
Seongwon
S
Park
Jong-Wan
JW
Ye
Sang-Kyu
SK
Chung
Myung-Hee
MH
D000818:Animals; D019556:COS Cells; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007511:Ischemia / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000502:physiology*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000502:physiology
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D050880:p300-CBP Transcription Factors