O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells
Standard
O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells. / Itkonen, Harri M; Minner, Sarah; Guldvik, Ingrid J; Sandmann, Mareike Julia; Tsourlakis, Maria Christina; Berge, Viktor; Svindland, Aud; Schlomm, Thorsten; Mills, Ian G.
in: CANCER RES, Jahrgang 73, Nr. 16, 15.08.2013, S. 5277-87.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells
AU - Itkonen, Harri M
AU - Minner, Sarah
AU - Guldvik, Ingrid J
AU - Sandmann, Mareike Julia
AU - Tsourlakis, Maria Christina
AU - Berge, Viktor
AU - Svindland, Aud
AU - Schlomm, Thorsten
AU - Mills, Ian G
PY - 2013/8/15
Y1 - 2013/8/15
N2 - Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked β-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.
AB - Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked β-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.
KW - Androgens
KW - Cell Cycle
KW - Cell Line, Tumor
KW - Cell Survival
KW - DNA Replication
KW - Hexosamines
KW - Humans
KW - Male
KW - Metabolic Networks and Pathways
KW - N-Acetylglucosaminyltransferases
KW - Prostatic Neoplasms
KW - Proto-Oncogene Proteins c-myc
KW - Receptors, Androgen
KW - Small Molecule Libraries
KW - Tumor Markers, Biological
KW - Up-Regulation
U2 - 10.1158/0008-5472.CAN-13-0549
DO - 10.1158/0008-5472.CAN-13-0549
M3 - SCORING: Journal article
C2 - 23720054
VL - 73
SP - 5277
EP - 5287
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 16
ER -