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Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAF V600E by synergistically decreasing global trimethylation of H3K27

2020; Wiley; Volume: 24; Issue: 6 Linguagem: Inglês

10.1111/jcmm.15007

1582-4934

Hao Fu, Lin Cheng, Ri Sa, Yuchen Jin, Libo Chen,

Cancer-related Molecular Pathways

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 V600E ‐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 V600E ‐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 V600E mutant cells, which was robustly strengthened by tazemetostat incorporation. Mechanically, MAPKi‐induced decrease of trimethylation of H3K27 was evidently intensified by tazemetostat in BRAF V600E ‐mutant cells. In conclusion, tazemetostat combined with MAPKi enhances differentiation of PTC cells harbouring BRAF V600E through synergistically decreasing global trimethylation of H3K27, representing a novel differentiation strategy.