Abstract A56: Tumor alarm gene FHIT activates tumor suppressive system by self-scarifying

Abstract

Human fragile histidine triad (FHIT) is known to be a putative tumor suppressor gene because of frequent deletion and mutation in various kinds of human cancers, in particular, human lung cancer. However, its biological function as tumor suppressor gene, has not been demonstrated. In fact, there are conflict results on the role of FHIT. Oncogenic property of FHIT has been proposed such as overeactivation of ATR/CHK1 pathway in FHIT deficient cells, and low tumor incidence in FHIT-deficient mice. In contrast, tumor suppressive functions such as cell cycle inhibition and induction of apoptosis also proposed. Here we provide the evidences about unexpected working mechanism of FHIT as a tumor alarm gene. FHIT can awake the intracellular tumor suppressive system through reduction or deletion itself. FHIT reduction or deleted cells significantly increase the p21/WAF1 expression as well as p14/ARF-p53. It is achieved at posttranslation level and p53-dependent manner. So loss of FHIT can sequester the cell cycle in G1 phase. FHIT reduction can be achieved by oncogene activation and DNA damage. Thus, FHIT-deficient cells did not response to additional tumor risk and accumulation of additional genetic mutation is easily fixed in genome, which may contribute to tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A56.