TY - JOUR
T1 - Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype
AU - Xiang, Lisha
AU - Gilkes, Daniele M.
AU - Hu, Hongxia
AU - Takano, Naoharu
AU - Luo, Weibo
AU - Lu, Haiquan
AU - Bullen, John W.
AU - Samanta, Debangshu
AU - Liang, Houjie
AU - Semenza, Gregg L.
PY - 2014
Y1 - 2014
N2 - Intratumoral hypoxia, which is associated with breast cancer metastasis and patient mortality, increases the percentage of breast cancer stem cells (BCSCs) but the underlying molecular mechanisms have not been delineated. Here we report that hypoxia-inducible factor 1 (HIF-1) triggers the expression and activity of TAZ, a transcriptional co-activator that is required for BCSC maintenance, through two discrete mechanisms. First, HIF-1 binds directly to the WWTR1 gene and activates transcription of TAZ mRNA. Second, HIF-1 activates transcription of the SIAH1 gene, which encodes a ubiquitin protein ligase that is required for the hypoxia-induced ubiquitination and proteasome-dependent degradation of LATS2, a kinase that inhibits the nuclear localization of TAZ. Inhibition of HIF-1α, TAZ, or SIAH1 expression by short hairpin RNA blocked the enrichment of BCSCs in response to hypoxia. Human breast cancer database analysis revealed that increased expression (greater than the median) of both TAZ and HIF-1 target genes, but neither one alone, is associated with significantly increased patient mortality. Taken together, these results establish a molecular mechanism for induction of the BCSC phenotype in response to hypoxia.
AB - Intratumoral hypoxia, which is associated with breast cancer metastasis and patient mortality, increases the percentage of breast cancer stem cells (BCSCs) but the underlying molecular mechanisms have not been delineated. Here we report that hypoxia-inducible factor 1 (HIF-1) triggers the expression and activity of TAZ, a transcriptional co-activator that is required for BCSC maintenance, through two discrete mechanisms. First, HIF-1 binds directly to the WWTR1 gene and activates transcription of TAZ mRNA. Second, HIF-1 activates transcription of the SIAH1 gene, which encodes a ubiquitin protein ligase that is required for the hypoxia-induced ubiquitination and proteasome-dependent degradation of LATS2, a kinase that inhibits the nuclear localization of TAZ. Inhibition of HIF-1α, TAZ, or SIAH1 expression by short hairpin RNA blocked the enrichment of BCSCs in response to hypoxia. Human breast cancer database analysis revealed that increased expression (greater than the median) of both TAZ and HIF-1 target genes, but neither one alone, is associated with significantly increased patient mortality. Taken together, these results establish a molecular mechanism for induction of the BCSC phenotype in response to hypoxia.
KW - Aldefluor assay
KW - Basal-like breast cancer
KW - Mammospheres
KW - Targeted therapy
KW - Triple-negative breast cancer
UR - http://www.scopus.com/inward/record.url?scp=84921374070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921374070&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.2997
DO - 10.18632/oncotarget.2997
M3 - Article
C2 - 25587023
AN - SCOPUS:84921374070
SN - 1949-2553
VL - 5
SP - 12509
EP - 12527
JO - Oncotarget
JF - Oncotarget
IS - 24
ER -