Cancer immunoediting enriches NANOG expression in tumor cells, resulting in multi-drug resistance and stem-like phenotypes. We previously demonstrated that these NANOG-associated phenotypes are promoted through HDAC1 transcriptional upregulation. In this study, we identified that NANOG also contributes to the stabilization of HDAC1 protein through the AKT signaling pathway. NANOG-AKT axis leads to phosphor-dependent inactivation of CHFR, an E3 ligase for HDAC1 protein, and thereby inhibiting the ubiquitin-mediated degradation of HDAC1. Furthermore, AKT inhibition disrupts HDAC1 WT-mediated phenotypes but had no effect on the phenotypes mediated by HDAC1 FM, a mutant that is unable to interact with CHFR. Critically, we applied a catalytic dead mutant, HDAC1-H141A, to uncover that HDAC1 confers immune-resistance, drug-resistance and stem-like phenotype in tumor cells through its catalytic activity. Collectively, our results establish a firm molecular link in immune-edited tumor cells among NANOG, AKT, CHFR, and HDAC1, identifying HDAC1 as a molecular target in controlling NANOGHIGH immune-refractory cancer.
|Number of pages
|Biochemical and biophysical research communications
|Published - 2018 Sept 10
Bibliographical noteFunding Information:
This work was supported by funding from the National Research Foundation of Korea ( 2017R1A2A1A17069818 and NRF-2017R1D1A1B03035438 ). p3 × FLAG CMV10 CHFR was kindly provided by Dr. Seol of Seoul National University.
© 2018 Elsevier Inc.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology