TY - JOUR
T1 - Human enhancer of filamentation 1 is a mediator of hypoxia-inducible factor-1α-mediated migration in colorectal carcinoma cells
AU - Kim, Sun Hee
AU - Xia, Dianren
AU - Kim, Sang Wook
AU - Holla, Vijaykumar
AU - Menter, David G.
AU - DuBois, Raymond N.
PY - 2010/5/15
Y1 - 2010/5/15
N2 - Human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is a scaffolding protein that is implicated in regulating diverse cellular processes, such as cellular attachment, motility, cell cycle progression, apoptosis, and inflammation. Here, we identify HEF1 as a novel hypoxia-inducible factor-1α (HIF-1α)-regulated gene and reveal that HEF1 mediates hypoxia-induced migration of colorectal carcinoma cells. HEF1 is highly expressed in cultured colorectal carcinoma cells exposed to hypoxia and in the hypoxic areas of human colorectal cancer (CRC) specimens. Moreover, our data show that HIF-1α mediates the effects of hypoxia on induction of HEF1 expression via binding to a hypoxia-responsive element of the HEF1 promoter. Importantly, the induction of HEF1 expression significantly enhances hypoxia-stimulated HIF-1α transcriptional activity by modulating the interaction between HIF-1α and its transcriptional cofactor p300. Inhibition of HEF1 expression also reduced the levels of hypoxia-inducible genes, including those that regulate cell motility. Cell migration was reduced dramatically following knockdown of HEF1 expression under hypoxic conditions. Thus, this positive feedback loop may contribute to adaptive responses of carcinoma cells encountering hypoxia during cancer progression.
AB - Human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is a scaffolding protein that is implicated in regulating diverse cellular processes, such as cellular attachment, motility, cell cycle progression, apoptosis, and inflammation. Here, we identify HEF1 as a novel hypoxia-inducible factor-1α (HIF-1α)-regulated gene and reveal that HEF1 mediates hypoxia-induced migration of colorectal carcinoma cells. HEF1 is highly expressed in cultured colorectal carcinoma cells exposed to hypoxia and in the hypoxic areas of human colorectal cancer (CRC) specimens. Moreover, our data show that HIF-1α mediates the effects of hypoxia on induction of HEF1 expression via binding to a hypoxia-responsive element of the HEF1 promoter. Importantly, the induction of HEF1 expression significantly enhances hypoxia-stimulated HIF-1α transcriptional activity by modulating the interaction between HIF-1α and its transcriptional cofactor p300. Inhibition of HEF1 expression also reduced the levels of hypoxia-inducible genes, including those that regulate cell motility. Cell migration was reduced dramatically following knockdown of HEF1 expression under hypoxic conditions. Thus, this positive feedback loop may contribute to adaptive responses of carcinoma cells encountering hypoxia during cancer progression.
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U2 - 10.1158/0008-5472.CAN-09-2110
DO - 10.1158/0008-5472.CAN-09-2110
M3 - Article
C2 - 20442290
AN - SCOPUS:77952863907
SN - 0008-5472
VL - 70
SP - 4054
EP - 4063
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -