Abstract 4074: Alterations of NDP kinase A/ NM23-H1 deregulate c-myc transcription

Abstract

Abstract Altered expression and mutations of NDP kinase A (NDPK-A), encoded by nm23-H1, have been detected in patients with metastatic tumors. One of new functions of NDPK-A is to participate in gene regulation. However, its role in regulating c-myc transcription remains unclear. Here we demonstrate for the first time that NDPK-A specifically bound nuclease hypersensitive element (NHE) III1 of the c-myc promoter in vitro and in vivo. Metastasis-associated S120G mutation of NDPK-A (NDPK-AS120G), but not S120G and N82S double mutations (NDPK-AS120G/N82S), retained the DNA-binding activity. In human NB69 neuroblastoma and HeLa cervical cancer cells, a high level of ectopic NDPK-A or NDPK-AS120 suppressed c-myc transcription based on the CAT reporter and RT-PCR. In contrast, shRNA-mediated knockdown of NDPK-A enhanced c-myc transcription. Without the DNA-binding activity, however, NDPK-AS120G/N82S did not display an effect on c-myc transcription. NDPK-A appears to exert transcriptional suppression via not only NHE III1 but also upstream cis-element(s) of c-myc promoter. The role of NDPK-A in regulating c-myc transcription was supported by nuclear localization of NDPK-A in cells and by negative correlation of NDPK-A and c-myc mRNA levels in several human cancer subtypes. Our findings provide a link between NDPK-A alterations and c-myc transcriptional deregulation in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4074.