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UBE2S inhibits colorectal cancer proliferation by regulating the PI3K/AKT and MAPK/ERK pathways via TRAF6

Jun Li^1,2, Haoran Feng^1,2, Kun Liu¹

¹Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Scientific Reports

|October 13, 2025

Abstract:

Ubiquitin conjugating enzyme UBE2S is an important enzyme in ubiquitin mediated proteolysis. The mechanisms of UBE2S in the colorectal cancer (CRC) proliferation need further exploration for new ubiquitination-related drugs exploitation. Firstly, we performed immunohistochemistry of UBE2S protein on CRC and adjacent tissues and found that UBE2S protein expressed higher in adjacent tissues than in tumor. TCGA and GTEx databases revealed a positive correlation between UBE2S expression and overall survival rate in CRC (P < 0.05). Cell proliferation experiments on HCT116 and RKO cell lines invalidated that UBE2S overexpression inhibited CRC cell proliferation and progression from G0/1 phase to G2 phase while knocking down UBE2S enhanced it. Mechanistically, combined with enrichment analysis based on RNA sequencing, it was identified molecularly that UBE2S simultaneously inhibited the activation of MAPK/ERK and PI3K/AKT pathways through promoting the ubiquitin-mediated degradation of TRAF6 protein, an upstream molecule to activate the both pathways, which can be blocked by inhibitor MG132. Animal experiments demonstrated that knocking down UBE2S resulted in larger transplanted tumor volumes than the control group, while overexpressing UBE2S resulted in the smaller ones in vivo. Summarily, we firstly identified that the UBE2S inhibited CRC proliferation by negatively regulating MAPK/ERK and PI3K/AKT/mTOR pathways through ubiquitinating TRAF6 protein.

Insights

Ubiquitin conjugating enzyme UBE2S inhibits colorectal cancer (CRC) proliferation. UBE2S targets TRAF6 for degradation, downregulating MAPK/ERK and PI3K/AKT pathways, offering potential therapeutic strategies for CRC treatment.

Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

Ubiquitin conjugating enzyme UBE2S plays a role in protein degradation.
Understanding UBE2S mechanisms in colorectal cancer (CRC) is crucial for developing new ubiquitination-related drugs.
The precise role of UBE2S in CRC proliferation requires further investigation.

Purpose of the Study:

To investigate the role and mechanism of UBE2S in colorectal cancer (CRC) proliferation.
To explore the potential of UBE2S as a therapeutic target for CRC.

Main Methods:

Immunohistochemistry on CRC and adjacent tissues.
Analysis of TCGA and GTEx databases for UBE2S expression and survival correlation.
Cell proliferation assays in HCT116 and RKO cell lines.
RNA sequencing and enrichment analysis.
Animal experiments with transplanted tumors.

Main Results:

UBE2S expression was higher in adjacent tissues than in tumor tissues.
Higher UBE2S expression correlated with better overall survival in CRC patients.
UBE2S overexpression inhibited CRC cell proliferation and G0/1 to G2 phase transition.
Knockdown of UBE2S enhanced CRC cell proliferation and progression.
UBE2S inhibited MAPK/ERK and PI3K/AKT pathways by promoting TRAF6 degradation.
In vivo studies showed UBE2S knockdown increased tumor volume, while overexpression decreased it.

Conclusions:

UBE2S inhibits CRC proliferation by negatively regulating MAPK/ERK and PI3K/AKT/mTOR pathways.
This regulation occurs through the ubiquitin-mediated degradation of TRAF6 protein.
UBE2S represents a potential therapeutic target for colorectal cancer.

Read full analysis

Keywords:

Colorectal cancer Proliferation TRAF6 UBE2S Ubiquitination

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