Oncotarget

Research Papers:

Downregulation of BRCA1-BRCA2-containing complex subunit 3 sensitizes glioma cells to temozolomide

Kit Man Chai _, Chih-Yen Wang, Hung-Jiun Liaw, Kuan-Min Fang, Chung-Shi Yang and Shun-Fen Tzeng

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Oncotarget. 2014; 5:10901-10915. https://doi.org/10.18632/oncotarget.2543

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Abstract

Kit Man Chai1, Chih-Yen Wang1, Hung-Jiun Liaw1, Kuan-Min Fang1, Chung-Shi Yang2, Shun-Fen Tzeng1

1 Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan City, 70101, Taiwan

2Center for Nanomedicine Research, National Health Research Institutes, Zhunan, 35053, Taiwan

correspondence to:

Shun-Fen Tzeng, e-mail: [email protected]

Key words: BRCC3, BRCC36, γH2AX, DNA repair, Glioblastoma

Received: July 26, 2014     Accepted: September 29, 2014     Published: October 07, 2014

ABSTRACT

We previously found that BRCA1-BRCA2-containing complex subunit 3 (BRCC3) was highly expressed in tumorigenic rat glioma cells. However, the functional role of BRCC3 in human glioma cells remains to be characterized. This study indicated that the upregulation of BRCC3 expression was induced in two human malignant glioblastoma U251 and A172 cell lines following exposure to the alkylating agent, temozolomide (TMZ). Homologous recombination (HR)-dependent DNA repair-associated genes (i.e. BRCA1, BRCA2, RAD51 and FANCD2) were also increased in U251 and A172 cells after treatment with TMZ. BRCC3 gene knockdown through lentivirus-mediated gene knockdown approach not only significantly reduced the clonogenic and migratory abilities of U251 and A172 cells, but also enhanced their sensitization to TMZ. The increase in phosphorylated H2AX foci (γH2AX) formation, an indicator of DNA damage, persisted in TMZ-treated glioma cells with stable knockdown BRCC3 expression, suggesting that BRCC3 gene deficiency is associated with DNA repair impairment. In summary, we demonstrate that by inducing DNA repair, BRCC3 renders glioma cells resistant to TMZ. The findings point to BRCC3 as a potential target for treatment of alkylating drug-resistant glioma.


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