STAT3-dependent systems-level analysis reveals PDK4 as an independent predictor of biochemical recurrence in prostate cancer

Oberhuber, M.; Pecoraro, M.; Rusz, M.; Oberhuber, G.; Wieselberg, M.; Haslinger, P.; Gurnhofer, E.; Pencik, J.; Wiebringhaus, R.; Schlederer, M.; Weiss, T.; Schmeidl, M.; Haitel, A.; Brehme, M. J.; Wadsak, W.; Griss, J.; Mohr, T.; Hofer, A.; Jäger, A.; Egger, G.; Pollheimer, J.; Koellensperger, G.; Mann, M.; Hantusch, B.; Kenner, L.

doi:10.1101/770701

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bioRxiv · 10.1101/770701

STAT3-dependent systems-level analysis reveals PDK4 as an independent predictor of biochemical recurrence in prostate cancer

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Abstract

Prostate cancer (PCa) has a broad spectrum of clinical behaviour, hence biomarkers are urgently needed for risk stratification. We previously described the protective effect of STAT3 in a prostate cancer mouse model. By utilizing a gene co-expression network in addition to laser microdissected proteomics from human and murine prostate FFPE samples, we describe STAT3-induced downregulation of the TCA cycle/OXPHOS in PCa on transcriptomic and proteomic level. We identify pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging and PSA level. Furthermore, PDK4 expression is causally linked to type 2 diabetes mellitus, which is known to have a protective effect on PCa. We conclude that this effect is related to PDK4 expression and that PDK4 loss could serve as a biomarker for PCa with dismal prognosis.

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Oberhuber, M., Pecoraro, M., Rusz, M., Oberhuber, G., Wieselberg, M., Haslinger, P., Gurnhofer, E., Pencik, J., Wiebringhaus, R., Schlederer, M., Weiss, T., Schmeidl, M., Haitel, A., Brehme, M. J., Wadsak, W., Griss, J., Mohr, T., Hofer, A., Jäger, A., Egger, G., Pollheimer, J., Koellensperger, G., Mann, M., Hantusch, B., Kenner, L.. 2019-09-19. STAT3-dependent systems-level analysis reveals PDK4 as an independent predictor of biochemical recurrence in prostate cancer. https://doi.org/10.1101/770701

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