TY - JOUR
T1 - Tumor-suppressive activity of lunatic fringe in prostate through differential modulation of notch receptor activation
AU - Zhang, Shubing
AU - Chung, Wen Cheng
AU - Wu, Guanming
AU - Egan, Sean E.
AU - Xu, Keli
N1 - Funding Information:
Address all correspondence to: Keli Xu, PhD, Cancer Institute, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. E-mail: kxu@umc.edu 1This work was supported by start-up funds from the Cancer Institute of the University of Mississippi Medical Center and by the National Institutes of Health (R21 CA175136) to K.X. and by funds from the Canadian Cancer Society Research Institute to S.E.E. The authors declare no conflict of interest. Received 7 November 2013; Revised 6 January 2014; Accepted 17 January 2014 Copyright © 2014 Neoplasia Press, Inc. All rights reserved 1522-8002/14/$25.00 DOI 10.1593/neo.131870
PY - 2014/2
Y1 - 2014/2
N2 - 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-β-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, associatedwith 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.
AB - 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-β-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, associatedwith 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.
UR - http://www.scopus.com/inward/record.url?scp=84900446105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84900446105&partnerID=8YFLogxK
U2 - 10.1593/neo.131870
DO - 10.1593/neo.131870
M3 - Article
C2 - 24709423
AN - SCOPUS:84900446105
SN - 1522-8002
VL - 16
SP - 158
EP - 167
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 2
ER -