Abstract
ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM and BRCA1 gene expression in head and neck cancer (HNC) is not well characterized. Here, we examined the prognostic role of ATM and BRCA1 expression in two HNC cohorts with and without betel quid (BQ) exposure. The results showed that the expression of ATM and BRCA1 was downregulated in BQ-associated HNC, as the BQ ingredient arecoline could suppress the expression of both genes. Low expression of either ATM or BRCA1 was correlated with poor overall survival (OS) and was an independent prognostic factor in multivariate analysis (ATM HR: 1.895, p = 0.041; BRCA1 HR: 2.163, p = 0.040). The combination of ATM and BRCA1 expression states further improved on the prediction of OS (HR: 4.195, p = 0.001, both low vs. both high expression). Transcriptomic analysis showed that inhibition of ATM kinase by KU55933 induced apoptosis signaling and potentiated cisplatin-induced cytotoxicity. These data unveil poor prognosis in the HNC patient subgroup with low expression of ATM and BRCA1 and support the notion of ATM-targeted therapy.
Highlights
DNA repair genes function as an anti-cancer barrier in the early stage of tumorigenesis [1,2]
To explore the effects of Areca Nut Extract (ANE) and arecoline on the expression of ataxia telangiectasia mutated (ATM) and BRCA1, we first extracted the microarray data of ANE (5 μg/mL, 72 h)-treated human gingival fibroblasts from the Gene Expression Omnibus (GEO, GSE59414) [45] and found that both ATM and BRCA1 mRNA expressions were downregulated by ANE treatment (Figure 1A)
The results showed that arecoline suppressed the expression of ATM and BRCA1 mRNAs in HEp-2, KB, and
Summary
DNA repair genes function as an anti-cancer barrier in the early stage of tumorigenesis [1,2]. In response to DNA damage, the ataxia telangiectasia mutated (ATM) kinase quickly phosphorylates histone H2A.X (γ-H2AX) and downstream targets, such as p53, BRCA1, and CHEK1/2, resulting in activation of the DNA damage response (DDR) that halts the cell cycle and initiates DNA repair process [3]. In addition to the role in DNA repair, BRCA1 is involved in the control of gene expression, cell cycle checkpoint, and centrosome duplication to keep genome integrity [4,5,6]. Cancer cells with low expression of BRCA1 are sensitive to DNA-damaging agents, such as cisplatin, but are resistant to spindle poisons, such as taxol [15,16]. The expression of BRCA1 can serve as a prognostic biomarker in breast, ovarian, lung, and colorectal cancers [10,17,18,19]
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