Transcriptomal profiling of the cellular response to DNA damage mediated by Slug (Snai2)

Abstract

Snai2-deficient cells are radiosensitive to DNA damage. The function of Snai2 in response to DNA damage seems to be critical for its function in normal development and cancer. Here, we applied a functional genomics approach that combined gene-expression profiling and computational molecular network analysis to obtain global dissection of the Snai2-dependent transcriptional response to DNA damage in primary mouse embryonic fibroblasts (MEFs), which undergo p53-dependent growth arrest in response to DNA damage. Although examination of the response showed that overall expression of p53 target gene expression patterns was similarly altered in both control and Snai2-deficient cells, we have identified and validated candidate Snai2 target genes linked to Snai2 gene function in response to DNA damage. This work defines for the first time the effect of Snai2 on p53 target genes in cells undergoing growth arrest, elucidates the Snai2-dependent molecular network induced by DNA damage, points to novel putative Snai2 targets, and suggest a mechanistic model, which has implications for cancer management.

Integrated Proteomics and Genomics Analysis Reveals a Novel Mesenchymal to Epithelial Reverting Transition in Leiomyosarcoma through Regulation of Slug

“…A recent investigation of neuroblastoma showed that the down-regulation of Slug increased the sensitivity to apoptosis induced by imatinib mesylate, etoposide, and doxorubicin (31). Furthermore, Slug-deficient cells are radiosensitive to DNA damage treatment (32). Our current study suggests that Slug may represent a therapeutic target for leiomyosarcoma, and inhibition of Slug may lead to MErT in leiomyosarcoma and improved response to chemotherapy.…”

MicroRNA-203 inhibits cellular proliferation and invasion by targeting Bmi1 in non-small cell lung cancer

“…SNAI2 is a transcription factor that belongs to the E-box-motif family. It inhibits apoptosis by repressing p53-mediated transcription and promotes epithelial-mesenchymal transition by directly repressing E-cadherin (28,29). However, it is not clear whether there is an interaction between miR-203 and Bmi1 in NSCLC.…”

Aberrant Expression of Osteopontin and E-Cadherin Indicates Radiation Resistance and Poor Prognosis for Patients with Cervical Carcinoma

“…The second potential mechanisms may be that EMT transcription factors, such as Slug and Snail, increase tumor cells invasiveness and capacity for migration as well as confer radioresistance. Slug-mutant or Slug-deficient mice were deemed radiationsensitive; thus, Slug is also considered to contribute to tumor radioresistance (Inoue et al 2002;Perez-Losada et al 2003;Perez-Caro et al 2008) . Slug mediates tumor cell survival from lethal irradiation via activation of a stem cell factor (SCF)/c-Kit signaling pathway (Perez-Losada et al 2003), regulation of DNA damage repair (Perez-Caro et al 2008) and inhibition of apoptosis induced by irradiation (Inoue et al 2002).…”

“…Slug-mutant or Slug-deficient mice were deemed radiationsensitive; thus, Slug is also considered to contribute to tumor radioresistance (Inoue et al 2002;Perez-Losada et al 2003;Perez-Caro et al 2008) . Slug mediates tumor cell survival from lethal irradiation via activation of a stem cell factor (SCF)/c-Kit signaling pathway (Perez-Losada et al 2003), regulation of DNA damage repair (Perez-Caro et al 2008) and inhibition of apoptosis induced by irradiation (Inoue et al 2002). In addition, Snail is associated with apoptotic resistance (Vega et al 2004) and affects cellular resistance to radiation-induced apoptosis (Escriva et al 2008), resulting in radiation resistance.…”