Abstract 1115: NANOG-AKT signaling increases metastatic capacity via stabilizes HDAC1 protein through Chfr inactivation

Abstract Histone deacetylases (HDACs), in particular HDAC1, play an important role in tumor development and progression by modifying histone and non-histone proteins. Overexpression of HDAC1, as a cancer marker associated with poor prognosis. Nevertheless, the regulatory molecular mechanisms of HDAC1 expression remain largely unknown. Previously, we validated the correlation between the key pluripotency transcription factor NANOG and HDAC1 in immune-edited tumor cells by identifying that NANOG upregulates HDAC1 expression through its promotor occupancy. In this study, we further elucidated the mechanism that Nanog could regulate the Hdac1 protein level, as well as transcriptional level. Interestingly, we found that Nanog induces phosphorylation of an E3 ubiquitin ligase Chfr through Akt signaling, which results in the inactivation of Chfr. This decreases not only ubiquitinase activity but proteasomal degradation on Hdac1. Furthermore, accumulated Hdac1 on its own gives rise to metastatic capacity in cancer cells. Moreover, inhibition of Akt signaling is significantly effective at reversing HDAC1 mediated metastatic capacity in refractory cancer types. Taken together, we suggest a mechanistic rationale for the application of Akt inhibitors in HDAC1+ cancer treatment. Citation Format: Eunho Cho. NANOG-AKT signaling increases metastatic capacity via stabilizes HDAC1 protein through Chfr inactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1115.