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

Abstract

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.

• Authors: 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
• Journal: European review for medical and pharmacological sciences (Eur Rev Med Pharmacol Sci) Vol. 19 Issue 17 Pg. 3194-200 (Sep 2015) ISSN: 2284-0729 [Electronic] Italy
• PMID: 26400522 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARID1A protein, human
• DNA-Binding Proteins
• Nuclear Proteins
• Transcription Factors
• SKP Cullin F-Box Protein Ligases

Topics

• Apoptosis
• Cell Line, Tumor
• DNA Damage (genetics)
• DNA-Binding Proteins
• Humans
• Nuclear Proteins (genetics, metabolism)
• SKP Cullin F-Box Protein Ligases (genetics, metabolism)
• Stomach Neoplasms (pathology)
• Transcription Factors (genetics, metabolism)
• Transfection