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Mutual regulation between OGT and XIAP to control colon cancer cell growth and invasion
Hyeon Gyu Seo1, Han Byeol Kim1,2, Ji Young Yoon2
1Glycosylation Network Research Center, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
Abstract:
O-GlcNAc transferase (OGT) is an enzyme that catalyzes the O-GlcNAc modification of nucleocytoplasmic proteins and is highly expressed in many types of cancer. However, the mechanism regulating its expression in cancer cells is not well understood. This study shows that OGT is a substrate of the E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) which plays an important role in cancer pathogenesis. Although LSD2 histone demethylase has already been reported as an E3 ubiquitin ligase in lung cancer cells, we identified XIAP as the main E3 ubiquitin ligase in colon cancer cells. Interestingly, OGT catalyzes the O-GlcNAc modification of XIAP at serine 406 and this modification is required for the E3 ubiquitin ligase activity of XIAP toward specifically OGT. Moreover, O-GlcNAcylation of XIAP suppresses colon cancer cell growth and invasion by promoting the proteasomal degradation of OGT. Therefore, our findings regarding the reciprocal regulation of OGT and XIAP provide a novel molecular mechanism for controlling cancer growth and invasion regulated by OGT and O-GlcNAc modification.
Insights
X-linked inhibitor of apoptosis (XIAP) targets O-GlcNAc transferase (OGT) for degradation, suppressing colon cancer growth. O-GlcNAcylation of XIAP by OGT is crucial for this process, revealing a novel regulatory mechanism.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- O-GlcNAc transferase (OGT) is crucial for modifying proteins and is highly expressed in cancers.
- Mechanisms controlling OGT expression in cancer remain unclear.
Purpose of the Study:
- To elucidate the regulatory mechanism of OGT in colon cancer cells.
- To investigate the role of X-linked inhibitor of apoptosis (XIAP) in OGT regulation.
Main Methods:
- Investigated OGT as a substrate of the E3 ubiquitin ligase XIAP.
- Identified XIAP as the primary E3 ligase for OGT in colon cancer.
- Examined the reciprocal regulation between OGT and XIAP.
Main Results:
- OGT modifies XIAP at serine 406, enhancing XIAP's E3 ligase activity towards OGT.
- XIAP-mediated OGT degradation suppresses colon cancer cell growth and invasion.
- Demonstrated a novel reciprocal regulatory loop between OGT and XIAP.
Conclusions:
- XIAP is the key E3 ubiquitin ligase for OGT in colon cancer.
- O-GlcNAcylation of XIAP by OGT is essential for OGT degradation and tumor suppression.
- This reciprocal regulation offers a new therapeutic target for controlling cancer progression.
