DNA damage regulates ARID1A stability via SCF ubiquitin ligase in gastric cancer cells

Z.-H. Jiang, X.-W. Dong, Y.-C. Shen, H.-L. Qian, M. Yan, Z.-H. Yu, H.-B. He, C.-D. Lu, F. Qiu

Department of Gastrointestinal Surgery, and Department of Gastroenterology, Ningbo Medical Center, Li Huili Hospital, Ningbo, Zhejiang, China. Jiang-zhouhua@hotmail.com

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• Oncology

OBJECTIVE: The gene product of the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) is a member of the SWI/SNF adenosine triphosphate-dependent chromatin-remodeling complexes, which plays an essential role in controlling gene expression and is also involved in cancer development. ARID1A is frequently mutated in a wild variety of cancers and function as a tumor suppressor in several kinds of cancers. ARID1A was down-regulated in gastric cancer, and associated poor patient prognosis. However, how ARID1A protein is regulated in gastric cancer remains largely unknown.

MATERIALS AND METHODS: Here, we show that ARID1A protein is rapidly ubiquitinated and degradated in gastric cancer cells in response to DNA damage treatment.

RESULTS: Using genetic and pharmacologic Cullin inactivation coupled with in vitro ubiquitination assay, we demonstrate that ARID1A is a substrate of the Cullin-SKP1-F-box protein (SCF) complexes. Moreover, gastric cancer cells with forced expression of ARID1A showed an increased sensitivity to DNA damage reagents. Thus, our data uncovered a previous unknown posttranscriptional regulation of ARID1A by SCF E3 ligase in gastric cancer cells in DNA damage response.

CONCLUSIONS: These findings suggest ARID1A might be a promising drug target in gastric cancer treatment.

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