Tumor-suppressive activity of Lunatic Fringe in prostate through differential modulation of Notch receptor activation.
Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in regulation of prostate tumor initiation and progression. Here, we report a critical role for Lunatic Fringe (Lfng), which encodes an O-fucosylpeptide 3-ß-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats of Notch receptor proteins, in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression. Deletion of Lfng in mice caused altered Notch activation in the prostate, associated with elevated accumulation of Notch1, Notch2, and Notch4 intracellular domains, decreased levels of the putative Notch3 intracellular fragment, as well as increased expression of Hes1, Hes5, and Hey2. Loss of Lfng resulted in expansion of the basal layer, increased proliferation of both luminal and basal cells, and ultimately, prostatic intraepithelial neoplasia. The Lfng-null prostate showed down-regulation of prostatic tumor suppressor gene NKX3.1 and increased androgen receptor expression. Interestingly, expression of LFNG and NKX3.1 were positively correlated in publically available human prostate cancer data sets. Knockdown of LFNG in DU-145 prostate cancer cells led to expansion of CD44(+)CD24(-) and CD49f(+)CD24(-) stem/progenitor-like cell population associated with enhanced prostatosphere-forming capacity. Taken together, these data revealed a tumor-suppressive role for Lfng in the prostate through differential regulation of Notch signaling.
Cancer Institute, University of Mississippi Medical Center, Jackson, MS.
Shubing
S
Zhang
Cancer Institute, University of Mississippi Medical Center, Jackson, MS.
Wen-cheng
WC
Chung
Department of Medical Informatics and Clinical Epidemiology and Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, OR.
Guanming
G
Wu
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Sean E
SE
Egan
Cancer Institute, University of Mississippi Medical Center, Jackson, MS; Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS. Electronic address: kxu@umc.edu.
Keli
K
Xu
D000818:Animals; D049109:Cell Proliferation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016695:Glycosyltransferases / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011944:Receptors, Androgen / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C499374:NOTCH3 protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011944:Receptors, Androgen; D051880:Receptors, Notch; D014157:Transcription Factors; D016695:Glycosyltransferases; C498393:LFNG protein, human