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,1
Departments of
* Clinical Cancer Prevention,
Gastrointestinal Medical Oncology,
Pathology, and
Biostatistics and Applied Mathematics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
1Correspondence: Department of Clinical Cancer Prevention, Unit 1360, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009, USA. E-mail: ishureiqi{at}mdanderson.org
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, I., Zuo, X., Broaddus, R., Wu, Y., Guan, B., Morris, J. S., Lippman, S. M. The transcription factor GATA-6 is overexpressed in vivo and contributes to silencing 15-LOX-1 in vitro in human colon cancer
Key Words: transcriptional regulation • apoptosis
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