Epigenetic Inactivation of the Tumor Suppressor

Simple Summary Lung cancer is one of the most commonly diagnosed cancers worldwide and the most common cause of cancer-related deaths. During lung carcinogenesis, epigenetic alteration of tumor-related genes is a frequent event and especially silencing of tumor suppressor genes is often found. In our work, we identified Iroquois homeobox 1 (IRX1) from the lung cancer susceptibility locus 5p15.33, as an epigenetically silenced target gene. We report frequent epigenetic inactivation of IRX1 in primary lung adenocarcinoma. Moreover, reduced expression and hypermethylation of IRX1 was correlated with an impaired prognosis of patients with lung adenocarcinoma. Functionally, IRX1 overexpression induced signs of apoptosis including fragmented nuclei and expression of a proapoptotic regulator. Loss of IRX1 expression by its promoter hypermethylation can serve as a diagnostic and prognostic lung cancer biomarker. Abstract Iroquois homeobox (IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the IRX1 gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and function of IRX1 was investigated in lung carcinogenesis. We observed frequent hypermethylation of the IRX1 promoter in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC). Aberrant IRX1 methylation was significantly correlated with reduced IRX1 expression. In normal lung samples, the IRX1 promoter showed lower median DNA methylation levels (