title: Krüppel-like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen.
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. Deregulated expression of a number of Sp proteins has been associated with multiple types of human tumors, but 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 FBJ murine osteosarcoma viral oncogene homolog (FOS) and myelocytomatosis viral oncogene homolog (MYC) and with increased expression of telomerase reverse transcriptase (TERT) and the chromatin-modifying enzymes DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3). Expression of estrogen receptor alpha (ESR1) and the tumor-suppressor phosphatase and tensin homolog deleted in chromosome 10 (PTEN) 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.
authors.affiliation: Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202, USA.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Simmons
authors.forename: John Mark P
authors.initials: JM
authors.lastname: Pabona
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Heard
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Friedman
authors.forename: Michael T
authors.initials: MT
authors.lastname: Spataro
authors.forename: Amy L
authors.initials: AL
authors.lastname: Godley
authors.forename: Frank A
authors.initials: FA
authors.lastname: Simmen
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Burnett
authors.forename: Rosalia C M
authors.initials: RC
authors.lastname: Simmen
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004717:Endometrium / Q000166:cytology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged
chemical_list: D004967:Estrogens; C000715467:KLF4 protein, human; C489676:KLF9 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors