image: A lipid-rich and hypoxia tumor microenvironment elevates O-GlcNAc transferase (OGT) expression, catalyzing O-GlcNAcylation of the tumor suppressor PTEN. Specifically, O-GlcNAcylation of PTEN in T382 blocks phosphorylation at the same residue, promoting PTEN ubiquitination and degradation. This disruption of PTEN contributes to the progression of hepatocellular carcinoma (HCC).
Credit: Jianming Li
This study is led by Dr. Jianming Li and Dr. Jing Huang from the Department of Pathology at Soochow Medical College, Soochow University. It focuses on O-GlcNAcylation, a dynamic and reversible post-translational modification regulated by two key enzymes: O-GlcNAc Transferase (OGT), which adds the modification, and O-GlcNAcase (OGA), which removes it. This modification plays an important role in controlling protein stability, activity, and subcellular localization, and is involved in essential cellular processes such as metabolism and cell proliferation.
In this study, the researchers investigated the role of OGT-mediated O-GlcNAcylation in Metabolic Dysfunction-Associated Steatotic Liver Disease-related Hepatocellular Carcinoma (MASLD-HCC). They identified the tumor suppressor PTEN as a critical target of this modification.
Through analysis of patient samples and public databases, the team found that OGT expression is significantly higher in MASLD-HCC tissues compared to adjacent non-tumor tissues, and its high expression correlates with advanced tumor stages. Using liver-specific Ogt knockout mice and xenograft models, they demonstrated that OGT promotes liver tumor progression: deletion of Ogt slows tumor growth, while OGT overexpression accelerates tumor formation (see Figure 2).
Mechanistically, the researchers found that OGT directly interacts with PTEN and modifies it at the T382 residue. This O-GlcNAcylation exerts dual effects on PTEN: it competitively inhibits phosphorylation (a modification that stabilizes PTEN) at the same site, thereby promoting PTEN ubiquitination and proteasomal degradation; simultaneously, it impairs PTEN's intrinsic phospholipase activity. As a result, PTEN function is compromised, leading to activation of the PI3K/Akt signaling pathway and enhanced proliferation of liver cancer cells (see Figure 3).
Notably, the team also explored how the tumor microenvironment affect this pathway and its therapeutic implications. Under lipid-rich and hypoxic conditions (common features of liver tumors), OGT expression and PTEN O-GlcNAcylation are both elevated. To counter this effect, they tested the therapeutic potential of targeting OGT. Treatment with the OGT inhibitor OSMI-1 suppressed tumor growth and combining it with the PI3K inhibitor LY294002 produced an even greater antitumor effect. These results underscore the value of disrupting both metabolic regulators and downstream proliferative signaling in developing effective treatments for MASLD-related liver cancer (see Figure 4).
By comprehensively analyzing OGT's expression pattern, its regulation of PTEN, and its therapeutic potential, this study offers new insights into the molecular mechanisms driving MASLD-HCC. It identifies both OGT and PTEN as potential therapeutic targets and lays the groundwork for developing O-GlcNAcylation-based therapies for liver cancer associated with metabolic liver disease.
Journal
MedComm – Oncology
Article Title
O-GlcNAc Transferase Promotes Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Hepatocellular Carcinoma by Facilitating the Degradation of PTEN
Article Publication Date
14-Oct-2025