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Blockage of O-linked GlcNAcylation induces AMPK-dependent autophagy in bladder cancer cells.


ABSTRACT:

Background

High levels of the post-translational modification O-GlcNAcylation (O-GlcNAc) are found in multiple cancers, including bladder cancer. Autophagy, which can be induced by stress from post-translational modifications, plays a critical role in maintaining cellular homeostasis and regulating tumorigenesis. The impact of O-GlcNAcylation on autophagy in bladder cancer remains unclear. Here, we evaluate the change in autophagic activity in response to O-GlcNAcylation and explore the potential mechanisms.

Methods

O-GlcNAcylation levels in bladder cancer cells were altered through pharmacological or genetic manipulations: treating with 6-diazo-5-oxo-norleucine (DON) or thiamet-G (TG) or up- and downregulation of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA). Autophagy was determined using fluorescence microscopy and western blotting. Co-immunoprecipitation (Co-IP) assays were performed to evaluate whether the autophagy regulator AMP-activated protein kinase (AMPK) was O-GlcNAc modified.

Results

Cellular autophagic flux was strikingly enhanced as a result of O-GlcNAcylation suppression, whereas it decreased at high O-GlcNAcylation levels. Phosphorylation of AMPK increased after the suppression of O-GlcNAcylation. We found that O-GlcNAcylation of AMPK suppressed the activity of this regulator, thereby inhibiting ULK1 activity and autophagy.

Conclusion

We characterized a new function of O-GlcNAcylation in the suppression of autophagy via regulation of AMPK.

Graphical abstract

Blockage of O-linked GlcNAcylation induces AMPK dependent autophagy in bladder cancer cells.

SUBMITTER: Jin L 

PROVIDER: S-EPMC7063793 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Blockage of O-linked GlcNAcylation induces AMPK-dependent autophagy in bladder cancer cells.

Jin Lu L   Yuan Feng F   Dai Guangcheng G   Yao Qiu Q   Xiang Han H   Wang Lixia L   Xue Boxin B   Shan Yuxi Y   Liu Xiaolong X  

Cellular & molecular biology letters 20200310


<h4>Background</h4>High levels of the post-translational modification O-GlcNAcylation (O-GlcNAc) are found in multiple cancers, including bladder cancer. Autophagy, which can be induced by stress from post-translational modifications, plays a critical role in maintaining cellular homeostasis and regulating tumorigenesis. The impact of O-GlcNAcylation on autophagy in bladder cancer remains unclear. Here, we evaluate the change in autophagic activity in response to O-GlcNAcylation and explore the  ...[more]

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