The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis

Abstract

O-GlcNAcylation has been implicated in the tumorigenesis of various tissue origins, but its function in liver tumorigenesis is not clear. Here, we demonstrate that O-GlcNAcylation can enhance the expression, stability and function of Yes-associated protein (YAP), the downstream transcriptional regulator of the Hippo pathway and a potent oncogenic factor in liver cancer. O-GlcNAcylation induces transformative phenotypes of liver cancer cells in a YAP-dependent manner. An O-GlcNAc site of YAP was identified at Thr241, and mutating this site decreased the O-GlcNAcylation, stability, and pro-tumorigenic capacities of YAP, while increasing YAP phosphorylation. Importantly, we found via in vitro cell-based and in vivo mouse model experiments that O-GlcNAcylation of YAP was required for high-glucose-induced liver tumorigenesis. Interestingly, a positive feedback between YAP and global cellular O-GlcNAcylation is also uncovered. We conclude that YAP O-GlcNAcylation is a potential therapeutic intervention point for treating liver cancer associated with high blood glucose levels and possibly diabetes.

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

“…Recently, a link between glucose concentration and Hippo pathway activity has emerged, wherein glucose deprivation or bioenergetic stress activates AMPK and LATS1/2, which phosphorylate and inactivate Yap (DeRan et al , ; Enzo et al , ; Gailite et al , ; Mo et al , ; Wang et al , ). The importance of lipid and glucose levels in the regulation of the Hippo pathway is best exemplified by elegant work demonstrating the activation of TEAD and Yap directly by palmitoylation (Chan et al , ) and O‐GlcNAcylation (Zhang et al , ), respectively. Together, these studies indicate that Yap activity is tightly regulated by the energetic state of the cell, particularly lipid and glucose supply.…”

O‐GlcNAcylation promotes colorectal cancer progression by regulating protein stability and potential catcinogenic function of DDX5

“…(Figure A). Since O‐GlcNAcylation is reported to be an important factor affecting protein stability, we therefore investigated whether stimulation of O‐GlcNAcylation inhibits DDX5 degradation. To clarify whether down‐regulation of O‐GlcNAcylation alters the stability of DDX5, SW480 cells with or without OGT knockdown were treated with cycloheximide to inhibit protein synthesis, and then the remaining DDX5 was detected.…”

“…Clinical studies have also found that higher levels of O‐GlcNAcylation are involved in the malignant clinicopathological features of various cancer patients . In gastric carcinoma, poorly differentiated tumours (grades II and III) showed significantly higher expression of O‐GlcNAcylation than grade I tumours .…”

“…Protein O‐GlcNAcylation is a broad and dynamic modification of β‐N‐acetyl‐D‐glucosamine . It is a specific type of post‐translational modification catalysed by O‐linked N‐acetylglucosamine transferase (OGT), resulting in the transfer of O‐linked β‐N‐acetylglucosamine (O‐GlcNAcylation) to the serine of the target protein or threonine residue .…”

“…And regulate protein stability . Pathologically, abnormal O‐GlcNAcylation has been shown to stimulate tumorigenesis in various cancers by modulating cell signalling, transcription, cell division, metabolism, and cytoskeletal regulation …”