UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer

Abstract

Bone metastasis is the main site of metastasis and causes the most deaths in patients with prostate cancer (PCa). The mechanism of bone metastasis is complex and not fully clarified. By RNA sequencing and analysing key pathways in bone metastases of PCa, we found that one of the most important characteristics during PCa bone metastasis was G1/S transition acceleration caused by low protein levels of p16INK4a (p16). Interestingly, we demonstrated that UBE2S bound and degraded p16 through K11- rather than K48- or K63-linked ubiquitination, which accelerated PCa tumour cell G1/S transition in vivo and in vitro . Moreover, UBE2S also stabilized β-catenin through K11-linked ubiquitination, leading to enhanced migration and invasion of tumour cells in PCa bone metastasis. Based on our cohorts and public databases, UBE2S was overexpressed in bone metastases and positively correlated with a high Gleason score, advanced nodal metastasis status and poor prognosis in PCa. Finally, targeting UBE2S with cephalomannine inhibited proliferation and invasion in vitro , and bone metastasis of PCa in vivo . This study innovatively discovered that UBE2S plays an oncogenic role in bone metastasis of PCa by degrading p16 and stabilizing β-catenin via K11-linked ubiquitination, suggesting that it may serve as a multipotent target for metastatic PCa treatment.

TSPAN18 Facilitates Bone Metastasis of Prostate Cancer by Protecting STIM1 from TRIM32-Mediated Ubiquitination

“…Three-to four-weeks-old male BALB/c nude mice were obtained from Shanghai SLAC Laboratory Animal Co., Ltd. and housed in groups of one to ve per cage, with a standard 12-h light-dark cycle in a room maintained at 24 ℃ with free access to water and chow inside a barrier facility. A total of 2.5 × 10 6 of the indicated PC3 cells per mouse were injected into the caudal artery, in line with our previous study 30 . Bone metastasis was monitored and imaged weekly with a bioluminescence imaging system after tumor cell injection for six weeks.…”

Integrating single-cell and bulk RNA sequencing to predict prognosis and immunotherapy response in prostate cancer

“…MYC promoted PCa oncogenic signaling via the PI3K/AKT/mTOR pathway, thereby stimulating massive cancer cell growth 48 . The latest study con rmed that UBE2S could stabilize β-linked proteins by K16linked ubiquitination, leading to enhanced migration and invasion of tumor cells in PCa bone metastases and exerting oncogenic effects 49 . Although there is no direct evidence linking HOPX, LY6E, SAMD4A, and CRISPLD2 to the development of PCa, numerous studies have shown their close relationship with the growth and invasion of other tumours, such as colorectal, gastric, lung, and breast cancers [50][51][52][53] .…”

Identification of the hub and prognostic genes in liver hepatocellular carcinoma via bioinformatics analysis

“…Ubiquitin conjugating enzyme E2S ( UBE2S ), also known as E2EPF , belongs to the E2 family of proteins and elongates the K11-linked polyubiquitin chain on APC/C substrates for 26 S proteasome-mediated degradation to promote cell division ( Wu et al, 2010 ). UBE2S can promote the progression of many types of cancer, such as ovarian cancer ( Hu et al, 2021 ), non-small cell lung cancer ( Qin et al, 2020 ), colorectal cancer ( Li et al, 2018 ) and prostate cancer ( Peng et al, 2022 ). In addition, UBE2S promoted cell chemoresistance through PTEN-AKT signaling in HCC ( Gui et al, 2021 ), which indicated that UBE2S may be a novel oncogene in the development of cancer.…”