摘要：

Cancer cells increase nutrient consumption leading to the altered metabolic state known as the Warburg effect. One pathway dependent on glucose, glutamine and acetyl-CoA is the Hexosamine Biosynthetic Pathway (HBP). Increased flux through the HBP leads to elevated post-translation addition of O-linked-β-N-acetylglucosamine (O-GlcNAc) on a diverse population of nuclear and cytosolic proteins, many of which are implicated in cancer. Recently, our lab provided the first evidence that breast and prostate cancers increases total O-GlcNAcylation by increasing O-GlcNAc Transferase (OGT) levels. Importantly, reducing OGT activity inhibits cancer cell invasion in vitro and metastasis in vivo. OGT inhibition reduces breast and prostate cancer cell invasion through, in part, inhibition of the oncogenic transcription factor, FOXM1 and its transcriptional target matrix metalloproteinase 2 (MMP2). Here, we show that OGT regulation of FOXM1 and cancer cell invasion requires regulation of the NAD+-dependent deacetylase, SIRT1. SIRT1 is a NAD+-dependent deacetylase regulated by changes in energy metabolism and its levels have been found to be reduced during breast cancer progression. We demonstrate an inverse relationship between O-GlcNAcylation and SIRT1 protein level and activity in multiple breast cancer cells and show that SIRT1 regulation by O-GlcNAcylation occurs in an AMPK-dependent manner. Consistent with this idea that reducing O-GlcNAcylation increases SIRT1 activity, we found that reducing OGT levels results in increased NAD+ metabolite levels in breast cancer cells. Importantly, we demonstrate that SIRT1 is critical for OGT-mediated regulation of FOXM1 protein ubiquitination and proteosomal degradation as reducing SIRT1 levels or activity reverses OGT-mediated regulation of FOXM1 and invasion in aggressive triple negative breast cancer cells. Furthermore, we show that SIRT1 regulates FOXM1 to modulate its transcriptional target MMP2 to promote breast cancer cell invasion. Collectively, these data indicate that flux through HBP, via O-GlcNAcylation, connects this nutrient sensing pathways with SIRT deactylases to regulate cellular invasion signaling via regulation of FOXM1.

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