Activation of a Tip60/E2F1/ERCC1 network in human lung adenocarcinoma cells exposed to cisplatin

International audienceThe Tip60 and E2F1 proteins are key players of the cellular response induced by genotoxic stresses. Here, new insights into the involvement of both proteins during the DNA damage response are provided. We show that Tip60 interacts with E2F1 and promotes its acetylation. We identify the lysine residues 120/125 of the E2F1 protein as the prime target sites of Tip60 and show that acetylation at these sites promotes the accumulation of E2F1. Importantly, we demonstrate that cisplatin induces the accumulation of E2F1 in a Tip60-dependent manner. However, and in contrast to PCAF and p300, Tip60 is not required for the induction of apoptosis in cisplatin-treated cells. Instead, Tip60 and E2F1 are involved in the upregulation of the excision repair cross-complementation group 1 protein expression, an enzyme involved in the repair of cisplatin-induced DNA lesions. These findings identify Tip60 as a direct regulator of E2F1 and support their cooperative role in DNA repair

Expression of candidate tumor suppressor gene ING2 is lost in non-small cell lung carcinoma.

International audienceING2 is a candidate tumor suppressor gene involved in cell cycle control, apoptosis and senescence. Furthermore, we have recently shown that loss of ING2 expression is associated with increased genome instability. We investigated its status in a series of 120 non-small cell lung cancer (NSCLC) by using immunohistochemistry (IHC). The results showed that ING2 protein expression is downregulated in more than 50% of NSCLC, with a higher frequency in adenocarcinoma (ADK) as compared to squamous cell carcinoma (SCC) (68% versus 45%, P=0.021). Loss of ING2 expression occurs in a high proportion of tumors from stage I and was not associated with patient's gender, age and 5-year survival. When investigating the possible mechanisms responsible for the decrease of ING2 expression, we did not observe any loss of heterozygosity or mutation in the ING2 gene. However, in 95% of the cases examined, we identified a silent single nucleotide polymorphism (SNP). By using quantitative RT-PCR, we found that ING2 loss of expression may be due to the decrease of its mRNA level. Analysis of CpG islands present in the promoter region of the ING2 gene did not allow for the detection of methylation. Mechanistically, although p53 can regulate ING2 transcription and ING2 enhances p53 activity, no correlation between ING2 and p53 IHC status was observed. Overall, these results indicate that loss of ING2 expression could contribute to lung tumorigenesis independently of p53