The transcription factor GATA-6 is overexpressed in vivo and contributes to silencing 15-LOX-1 in vitro in human colon cancer.
Transcriptional suppression of 15-lipoxygenase (LOX)-1 (15-LOX-1) helps enable human colorectal cancer cells escape apoptosis, a critical mechanism for colonic tumorigenesis. GATA-6 is strongly expressed in vitro in cancer cells; its down-regulation by pharmaceuticals is associated with reversal of 15-LOX-1 transcriptional suppression. The mechanistic contribution of GATA-6 overexpression to colonic tumorigenesis, especially concerning 15-LOX-1 transcriptional suppression, remains unknown. We tested whether GATA-6 is differentially overexpressed in human colorectal cancers and whether reversing GATA-6 overexpression in colon cancer cells is sufficient to restore 15-LOX-1 expression and influence cell proliferation or apoptosis. The expression of GATA-6 RNA and protein was measured in paired human colorectal cancer and normal tissues from two separate patient groups. We used GATA-6 small interfering RNA transfection to down-regulate GATA-6 expression and examine the effects of this down-regulation on 15-LOX-1 expression, cell proliferation, and apoptosis in Caco-2 and HCT-116 colon cancer cells with and without the nonsteroidal antiinflammatory drug NS-398 or the histone deacetylase inhibitor sodium butyrate. GATA-6 mRNA and protein expressions were higher in cancer than normal epithelia of the colon. GATA-6 knockdown was insufficient by itself but contributed significantly to restoring 15-LOX-1 expression and inducing apoptosis by NS-398 or sodium butyrate. Maintaining 15-LOX-1 transcriptional silencing in cancer cells is a multifactorial process involving GATA-6 overexpression and other regulatory events.
Shureiqi
Imad
I
Department of Clinical Cancer Prevention, Unit 1360, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009, USA. ishureiqi@mdanderson.org
Zuo
Xiangsheng
X
Broaddus
Russell
R
Wu
Yuanqing
Y
Guan
Baoxiang
B
Morris
Jeffrey S
JS
Lippman
Scott M
SM
D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics*; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000473:pathology; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D014407:Tumor Cells, Cultured
D050993:GATA6 Transcription Factor; D001093:Arachidonate 15-Lipoxygenase