Stabilization of HDAC1 via TCL1-pAKT-CHFR axis is a key element for NANOG-mediated multi-resistance and stem-like phenotype in immune-edited tumor cells.

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.
Mesh Terms:
Cell Cycle Proteins, Cell Line, Tumor, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Female, HEK293 Cells, HeLa Cells, Histone Deacetylase 1, Humans, Mutagenesis, Site-Directed, Nanog Homeobox Protein, Neoplasm Proteins, Phenotype, Poly-ADP-Ribose Binding Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Ubiquitin-Protein Ligases, Uterine Cervical Neoplasms
Biochem. Biophys. Res. Commun.
Date: Dec. 10, 2017
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