Mutant p53 cooperates with ETS2 to promote etoposide resistance

• Published in: Genes & development 2012-04, Vol.26 (8), p.830-845
• Main Authors: Do, Phi M, Varanasi, Lakshman, Fan, Songqing, Li, Chunyang, Kubacka, Iwona, Newman, Virginia, Chauhan, Krishna, Daniels, Silvano Rakeem, Boccetta, Maurizio, Garrett, Michael R, Li, Runzhao, Martinez, Luis A
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Cell Line, Tumor; Drug Resistance, Neoplasm; Etoposide - pharmacology; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proto-Oncogene Protein c-ets-2 - metabolism; Research Paper; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.181685.111

Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable" component of mtp53's gain-of-function activity.