Location: Arkansas Children's Nutrition CenterTitle: Krüppel-Like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen Author
|Pabona, John Mark|
Submitted to: Biology of Reproduction
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/11/2011
Publication Date: 8/1/2011
Citation: Simmons, C.D., Pabona, J.P., Heard, M.E., Friedman, T., Michael, S., Godley, A.L., Simmen, F.A., Burnett, A., Simmen, R.C. 2011. Krüppel-Like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen. Biology of Reproduction. 85(2):378-385. Interpretive Summary: Cancer of the uterus is a devastating disease of women whose origin remains unclear. We evaluated the possible cause of this disease in women who are diagnosed with endometrial cancer. Examination of non-tumor (normal) uterus and of uterine tumors indicate that there are major differences in the patterns of expression of a number of genes involved in cell growth and death. We suggest that these genes may be involved in the development of endometrial cancer.
Technical Abstract: Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like Factor 9 (KLF9), a member of the evolutionarily conserved Sp-family of transcription factors, is expressed in uterine stroma and glandular epithelium where it affects cellular proliferation, differentiation and apoptosis. While deregulated expression of a number of Sp proteins has been associated with multiple types of human tumors, a role for KLF9 in endometrial cancer development and/or progression is unknown. Here, we evaluated KLF9 expression in endometrial tumors and adjacent uninvolved endometrium of women with endometrial carcinoma. KLF9 mRNA and protein levels were lower in endometrial tumors coincident with decreased expression of family member KLF4 and growth-regulators FOS and MYC and with increased expression of Telomerase Reverse Transcriptase (TERT) and chromatin-modifying enzymes DNA methyltransferase 1 (DNMT1) and Histone deacetylase (HDAC) 3. Estrogen Receptor-a (ESR1) and tumor suppressor PTEN expression did not differ between tumor and normal tissue. The functional relevance of attenuated KLF9 expression in endometrial carcinogenesis was further evaluated in the human endometrial carcinoma cell line Ishikawa by siRNA targeting. KLF9 depletion resulted in loss of normal cellular response to the proliferative effects of estrogen concomitant with reductions in KLF4 and MYC and with enhancement of TERT and ESR1 gene expression. Silencing of KLF4 did not mimic the effects of silencing KLF9 in Ishikawa cells. We suggest that KLF9 loss-of-expression accompanying endometrial carcinogenesis may predispose endometrial epithelial cells to mechanisms of escape from estrogen-mediated growth regulation leading to progression of established neoplasms.