Combined Tazemetostat and MAPKi Enhances Differentiation of Papillary Thyroid Cancer Cells Harbouring BRAF by Synergistically Decreasing Global Trimethylation of H3K27

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2020 Jan 24

PMID 31970877

Citations 18

Authors

Hao Fu

Lin Cheng

Ri Sa

Yuchen Jin

Libo Chen

Affiliations

Soon will be listed here.

Abstract

Clinical efficacy of differentiation therapy with mitogen-activated protein kinase inhibitors (MAPKi) for lethal radioiodine-refractory papillary thyroid cancer (RR-PTC) urgently needs to be improved and the aberrant trimethylation of histone H3 lysine 27 (H3K27) plays a vital role in BRAF -MAPK-induced cancer dedifferentiation and drug resistance. Therefore, dual inhibition of MAPK and histone methyltransferase (EZH2) may produce more favourable treatment effects. In this study, BRAF -mutant (BCPAP and K1) and BRAF-wild-type (TPC-1) PTC cells were treated with MAPKi (dabrafenib or selumetinib) or EZH2 inhibitor (tazemetostat), or in combination, and the expression of iodine-metabolizing genes, radioiodine uptake, and toxicity were tested. We found that tazemetostat alone slightly increased iodine-metabolizing gene expression and promoted radioiodine uptake and toxicity, irrespective of the BRAF status. However, MAPKi induced these effects preferentially in BRAF mutant cells, which was robustly strengthened by tazemetostat incorporation. Mechanically, MAPKi-induced decrease of trimethylation of H3K27 was evidently intensified by tazemetostat in BRAF -mutant cells. In conclusion, tazemetostat combined with MAPKi enhances differentiation of PTC cells harbouring BRAF through synergistically decreasing global trimethylation of H3K27, representing a novel differentiation strategy.

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