Molecular insights into lung cancer subtypes and therapeutic targeting approaches involving HDACi

4^th International Conference and Exhibition on Lung & Respiratory Care

August 01-02, 2016 Manchester, UK

Oliver H Kramer

University Medical Center Mainz, Germany

Posters & Accepted Abstracts: J Pulm Respir Med

Abstract :

The Janus tyrosine kinases JAK1-3 and tyrosine kinase-2 (TYK2) are frequently hyperactivated in tumors. In lung cancers JAK1 and JAK2 induce oncogenic signaling through STAT3. A putative role of TYK2 in these tumors has not been reported. We found a previously not recognized TYK2-STAT3 signaling node in lung cancer cells. We reveal that the E3 ubiquitin ligase sevenin- absentia-2 (SIAH2) accelerates the proteasomal degradation of TYK2. This mechanism consequently suppresses the activation of STAT3. In agreement with these data the analysis of primary non-small-cell lung cancer (NSCLC) samples from three patient cohorts revealed that compared to lung adenocarcinoma (ADC), lung squamous cell carcinoma (SCC) show significantly higher levels of SIAH2 and reduced STAT3 phosphorylation levels. Thus, SIAH2 is a novel molecular marker for SCC. We further demonstrate that an activation of the oncologically relevant transcription factor p53 in lung cancer cells induces SIAH2, depletes TYK2, and abrogates the tyrosine phosphorylation of STAT1 and STAT3. Moreover, we demonstrate that epigenetic modulators belonging to the class of histone deacetylase inhibitors (HDACi) modulate pro- and anti-metastatic gene expression patterns in tumor cells. These involve among other key molecules the surface molecules CD44 and E-Cadherin as well as the tyrosine kinase ACK1. Our studies may help to identify molecular mechanisms affecting lung carcinogenesis and potential therapeutic targets and strategies.

Biography :

Email: okraemer@uni-mainz.de