Abstract 8: Reptin is required for the transcription of telomerase reverse transcriptase and overexpressed in gastric cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Telomerase is activated in oncogenesis, which confers an immortal phenotype to cancer cells. The AAA+ ATPases Reptin and Pontin have recently been identified to be required for telomerase biogenesis by maintaining telomerase RNA (hTER) stability. Given their roles in chromatin remodeling and transcription regulation, we determined the effect of Reptin and Pontin on the transcription of the telomerase reverse transcriptase (hTERT) gene, a key component of the telomerase complex. The depletion of Reptin or Pontin in gastric and cervical cancer cells led to significant decreases in hTERT mRNA, but hTERT promoter activity was inhibited in only Reptin-depleted cells. Reptin interacted with the c-MYC oncoprotein and its stimulatory effect on the hTERT promoter was significantly dependent on functional E-boxes in the promoter. Moreover, Reptin bound to the hTERT proximal promoter and the loss of the Reptin occupancy led to dissociation of c-MYC from the hTERT promoter in Reptin-depleted cancer cells. We further demonstrated that Reptin inhibition dramatically impaired clonogenic potential of gastric cancer cells and that Reptin was over-expressed in primary gastric cancer specimens. Collectively, the hTERT gene is a direct target of Reptin, and hTERT transcription requires constitutive expression of Reptin and its cooperation with c-MYC. Thus Reptin regulates telomerase at two different levels. This finding, together with the requirement of Reptin for clonogenic potentials of cancer cells and its widespread over-expression in primary gastric cancer, suggests that Reptin may be a putative cancer therapeutic target. 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 8.