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O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells

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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, Vol. 73, No. 16, 15.08.2013, p. 5277-87.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Itkonen, HM, Minner, S, Guldvik, IJ, Sandmann, MJ, Tsourlakis, MC, Berge, V, Svindland, A, Schlomm, T & Mills, IG 2013, 'O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells', CANCER RES, vol. 73, no. 16, pp. 5277-87. https://doi.org/10.1158/0008-5472.CAN-13-0549

APA

Itkonen, H. M., Minner, S., Guldvik, I. J., Sandmann, M. J., Tsourlakis, M. C., Berge, V., Svindland, A., Schlomm, T., & Mills, I. G. (2013). O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells. CANCER RES, 73(16), 5277-87. https://doi.org/10.1158/0008-5472.CAN-13-0549

Vancouver

Itkonen HM, Minner S, Guldvik IJ, Sandmann MJ, Tsourlakis MC, Berge V et al. O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells. CANCER RES. 2013 Aug 15;73(16):5277-87. https://doi.org/10.1158/0008-5472.CAN-13-0549

Bibtex

@article{c2b2a66b2ec34a41bfbfd25296518b65,
title = "O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells",
abstract = "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.",
keywords = "Androgens, Cell Cycle, Cell Line, Tumor, Cell Survival, DNA Replication, Hexosamines, Humans, Male, Metabolic Networks and Pathways, N-Acetylglucosaminyltransferases, Prostatic Neoplasms, Proto-Oncogene Proteins c-myc, Receptors, Androgen, Small Molecule Libraries, Tumor Markers, Biological, Up-Regulation",
author = "Itkonen, {Harri M} and Sarah Minner and Guldvik, {Ingrid J} and Sandmann, {Mareike Julia} and Tsourlakis, {Maria Christina} and Viktor Berge and Aud Svindland and Thorsten Schlomm and Mills, {Ian G}",
year = "2013",
month = aug,
day = "15",
doi = "10.1158/0008-5472.CAN-13-0549",
language = "English",
volume = "73",
pages = "5277--87",
journal = "CANCER RES",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

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 -