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.

Heat stress and immune response phenotype affect DNA methylation in blood mononuclear cells from Holstein dairy cows

“…The promoter region with the lowest methylation density (hypomethylated) in HS samples was the multiple myeloma tumour-associated protein 2 ( MMTAG2 ) gene. Luo et al 93 showed that MMTAG2 (also known as C1orf35) is involved in cell growth by promoting cell cycle progression from G1 to S. Overexpression of MMTAG2 results in up-regulation of c-MYC and subsequent accelerated cell proliferation 94 , perhaps revealing a cell survival mechanism activated in low cows. The promoter regions of two histone deacetylases ( HDAC10 , HDAC4 ) were hypermethylated in HS samples from low cows.…”

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

“… 55 UBE2T is able to induce ubiquitination of RACK1 at the lysine K172 to enhance its degradation, leading to activation of Wnt/β-catenin and subsequent increase in gastric cancer progression. 56 β-catenin signaling also participates in drug resistance feature of cancer cells. 57 β-catenin is able to stimulate autophagy and mediate temozolomide resistance of glioblastoma.…”

Ubiquitin Proteasome Pathway Transcriptome in Epithelial Ovarian Cancer

“…UBE2T plays a key role in the ubiquitination of FANCD2 as part of the core FA complex; it also facilitates the assembly of the core FA complex [ 33 ]. Two recent reports described the identification of a UBE2T inhibitor with therapeutic potential [ 21 , 34 ]. The report of Cornwell et al [ 21 ] described a small molecule that specifically inhibited UBE2T/FANCL-induced ubiquitination of FANCD2.…”