Cell Metabolism Control Through O-GlcNAcylation of STAT5: A Full or Empty Fuel Tank Makes a Big Difference for Cancer Cell Growth and Survival.

Manuel Rauth,Patricia Freund,Anna Orlova,Richard Moriggl,Nikola Tasic,Xiaonan Han,Hai-Bin Ruan,Stefan Grünert,Heidi Neubauer

doi:10.3390/ijms20051028

Abstract

O-GlcNAcylation is a post-translational modification that influences tyrosine phosphorylation in healthy and malignant cells. O-GlcNAc is a product of the hexosamine biosynthetic pathway, a side pathway of glucose metabolism. It is essential for cell survival and proper gene regulation, mirroring the metabolic status of a cell. STAT3 and STAT5 proteins are essential transcription factors that can act in a mutational context-dependent manner as oncogenes or tumor suppressors. They regulate gene expression for vital processes such as cell differentiation, survival, or growth, and are also critically involved in metabolic control. The role of STAT3/5 proteins in metabolic processes is partly independent of their transcriptional regulatory role, but is still poorly understood. Interestingly, STAT3 and STAT5 are modified by O-GlcNAc in response to the metabolic status of the cell. Here, we discuss and summarize evidence of O-GlcNAcylation-regulating STAT function, focusing in particular on hyperactive STAT5A transplant studies in the hematopoietic system. We emphasize that a single O-GlcNAc modification is essential to promote development of neoplastic cell growth through enhancing STAT5A tyrosine phosphorylation. Inhibition of O-GlcNAcylation of STAT5A on threonine 92 lowers tyrosine phosphorylation of oncogenic STAT5A and ablates malignant transformation. We conclude on strategies for new therapeutic options to block O-GlcNAcylation in combination with tyrosine kinase inhibitors to target neoplastic cancer cell growth and survival.

Highlights

The metabolic state of tumor cells dramatically differs from the metabolism of healthy cells, and this largely defines the proliferation and expansion of malignancies
Recent cancer and immunology research has provided a better understanding of the consequences and advantages that changes in metabolic processes bring for normal or neoplastic cells [2,3,4]
As the uptake of these compounds is crucial, the intracellular concentration of these molecules increases. This leads to increased glycolysis in cancer cells and thereby an increased flux through the hexosamine biosynthetic pathway (HBP), which, in the end, provides the cell with uridine diphosphate-acetylglucosamine (UDP-GlcNAc)

Summary

Introduction

The metabolic state of tumor cells dramatically differs from the metabolism of healthy cells, and this largely defines the proliferation and expansion of malignancies. It is critical that activated JAK-STAT proteins are tightly regulated or silenced when cytokine or growth factor responses are terminated This is mainly achieved through the induction of negative feedback loops via suppressor of cytokine signaling (SOCS) proteins or tyrosine phosphatases. STAT proteins form homo- or heterodimers and translocate from the cell membrane into the nucleus, which is partly regulated by serine/threonine kinases They efficiently regulate transcription by binding to promoter and enhancer regions of cytokine-inducible genes, providing growth and survival signals as well as steering metabolism in a transient manner in normal cells, but persistently in cancer cells [9,10,14,26,27]

O-GlcNAcylation as an Essential Post-Translational Modification

O-GlcNAc is Crucial for JAK-STAT Pathway Functions