A novel UBE2T inhibitor suppresses Wnt/β-catenin signaling hyperactivation and gastric cancer progression by blocking RACK1 ubiquitination.

Abstract

Dysregulation of the Wnt/β-catenin signaling pathway is critically involved in gastric cancer (GC) progression. However, current Wnt pathway inhibitors being studied in preclinical or clinical settings for other cancers such as colorectal and pancreatic cancers are either too cytotoxic or insufficiently efficacious for GC. Thus, we screened new potent targets from β-catenin destruction complex associated with GC progression from clinical samples, and found that scaffolding protein RACK1 deficiency plays a significant role in GC progression, but not APC, AXIN, and GSK3β. Then, we identified its upstream regulator UBE2T which promotes GC progression via hyperactivating the Wnt/β-catenin signaling pathway through the ubiquitination and degradation of RACK1 at the lysine K172, K225, and K257 residues independent of an E3 ligase. Indeed, UBE2T protein level is negatively associated with prognosis in GC patients, suggesting that UBE2T is a promising target for GC therapy. Furthermore, we identified a novel UBE2T inhibitor, M435-1279, and suggested that M435-1279 acts inhibit the Wnt/β-catenin signaling pathway hyperactivation through blocking UBE2T-mediated degradation of RACK1, resulting in suppression of GC progression with lower cytotoxicity in the meantime. Overall, we found that increased UBE2T levels promote GC progression via the ubiquitination of RACK1 and identified a novel potent inhibitor providing a balance between growth inhibition and cytotoxicity as well, which offer a new opportunity for the specific GC patients with aberrant Wnt/β-catenin signaling.

• Authors: Zeyuan Yu, Xiangyan Jiang, Long Qin, Haixiao Deng, Jianli Wang, Wen Ren, Hongbin Li, Lei Zhao, Huanxiang Liu, Hong Yan, Wengui Shi, Qi Wang, Changjiang Luo, Bo Long, Huinian Zhou, Hui Sun, Zuoyi Jiao
• Journal: Oncogene (Oncogene) Vol. 40 Issue 5 Pg. 1027-1042 (02 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 33323973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Axin Signaling Complex
• CTNNB1 protein, human
• Neoplasm Proteins
• RACK1 protein, human
• Receptors for Activated C Kinase
• beta Catenin
• UBE2T protein, human
• Ubiquitin-Conjugating Enzymes

Topics

• Animals
• Axin Signaling Complex (genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Neoplasm Proteins (antagonists & inhibitors, genetics)
• Receptors for Activated C Kinase (antagonists & inhibitors, genetics)
• Stomach Neoplasms (drug therapy, genetics, pathology)
• Ubiquitin-Conjugating Enzymes (antagonists & inhibitors, genetics)
• Ubiquitination (drug effects)
• Wnt Signaling Pathway (genetics)
• Xenograft Model Antitumor Assays
• beta Catenin (genetics)