STAT3 and HIF1α cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells.

L Wang
L Wang
National Pingtung University of Science and Technology

Oncogene 2014 Mar 22;33(13):1670-9. Epub 2013 Apr 22.

1] Molecular Biology Graduate Program, Graduate School, University of Colorado Anschuts Medical Campus, Aurora, CO, USA [2] Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Solid tumors often exhibit simultaneously inflammatory and hypoxic microenvironments. The 'signal transducer and activator of transcription-3' (STAT3)-mediated inflammatory response and the hypoxia-inducible factor (HIF)-mediated hypoxia response have been independently shown to promote tumorigenesis through the activation of HIF or STAT3 target genes and to be indicative of a poor prognosis in a variety of tumors. We report here for the first time that STAT3 is involved in the HIF1, but not HIF2-mediated hypoxic transcriptional response. We show that inhibiting STAT3 activity in MDA-MB-231 and RCC4 cells by a STAT3 inhibitor or STAT3 small interfering RNA significantly reduces the levels of HIF1, but not HIF2 target genes in spite of normal levels of hypoxia-inducible transcription factor 1α (HIF1α) and HIF2α protein. Mechanistically, STAT3 activates HIF1 target genes by binding to HIF1 target gene promoters, interacting with HIF1α protein and recruiting coactivators CREB binding protein (CBP) and p300, and RNA polymerase II (Pol II) to form enhanceosome complexes that contain HIF1α, STAT3, CBP, p300 and RNA Pol II on HIF1 target gene promoters. Functionally, the effect of STAT3 knockdown on proliferation, motility and clonogenic survival of tumor cells in vitro is phenocopied by HIF1α knockdown in hypoxic cells, whereas STAT3 knockdown in normoxic cells also reduces cell proliferation, motility and clonogenic survival. This indicates that STAT3 works with HIF1 to activate HIF1 target genes and to drive HIF1-depedent tumorigenesis under hypoxic conditions, but also has HIF-independent activity in normoxic and hypoxic cells. Identifying the role of STAT3 in the hypoxia response provides further data supporting the effectiveness of STAT3 inhibitors in solid tumor treatment owing to their usefulness in inhibiting both the STAT3 and HIF1 pro-tumorigenic signaling pathways in some cancer types.

Download full-text PDF

Source Listing
March 2014
2 Reads
55 Citations
8.460 Impact Factor

Publication Analysis

Top Keywords

hif1 target
target genes
hypoxia response
clonogenic survival
cells stat3
rcc4 cells
motility clonogenic
gene promoters
stat3 knockdown
mda-mb-231 rcc4
target gene
proliferation motility
hypoxic cells
p300 rna
cbp p300
inhibiting stat3
activate hif1


(Supplied by CrossRef)
Article in Cancer Metastasis Rev
EC Finger et al.
Cancer Metastasis Rev 2010
Article in Nat Rev Cancer
B Keith et al.
Nat Rev Cancer 2012
Article in Cell
GL Semenza et al.
Cell 2012
Article in Cold Spring Harb Symp Quant Biol
WG Kaelin Jr et al.
Cold Spring Harb Symp Quant Biol 2011
Article in Oncogene
T Bowman et al.
Oncogene 2000
Article in Oncogene
J Bromberg et al.
Oncogene 2000
Article in J Urol
A Horiguchi et al.
J Urol 2002
Article in Nat Rev Cancer
H Yu et al.
Nat Rev Cancer 2004
Article in Trends Biochem Sci
CM Horvath et al.
Trends Biochem Sci 2000
Article in Breast
MY Lee et al.
Breast 2006
Article in J Immunol
MZ Noman et al.
J Immunol 2009

Similar Publications