Effect of KAT5/miR-210/TET2 pathway on radioresistance of anaplastic thyroid carcinoma / 中华放射肿瘤学杂志

ABSTRACT

Objective:To investigate the effect and mechanism of lysine acetyltransferase 5(KAT5) on the radio-sensitivity of anaplastic thyroid carcinoma (ATC).Methods:The expression levels of endogenous KAT5 in ATC and normal thyroid cells were detected by Western blot and qRT-PCR. The effect of KAT5 specific inhibitor NU9056 on the radio-sensitivity of human ATC cells and normal thyroid cells was evaluated by colony formation assay. TCGA database, JASPAR database, along with Western blot, microRNA sequencing, qRT-PCR and dual-luciferase reporter assay were conducted to unravel the underlying mechanism.Results:The expression of endogenous KAT5 at the protein and mRNA levels in human ATC cells was significantly higher than that in normal thyroid cells. NU9056 could significantly enhance the radiosensitivity of human ATC cells to 8505C and CAL-62, whereas showed no sensitization effect on normal thyroid cell Nthy-ori 3-1. Knockdown of KAT5 and NU9056 both down-regulated the expression level of miR-210 in the TC cells, while NU9056 decreased the expression level of transcription factor c-Myc. The putative binding sites of c-Myc in the miR-210 promoter region were predicted, and transfection of c-Myc plasmid significantly enhanced the luciferase activity of miR-210 promoter. Elevated miR-210 level was associated with worse survival of patients with thyroid carcinoma. Down-regulated expression of miR-210 decreased the TET2 mRNA level, while inhibition of miR-210 increased the TET2 mRNA level.Conclusion:The aberrantly-activated KAT5/miR-210/TET2 pathway probably causes the radioresistance of ATC, becoming a novel sensitizing target for ATC radiotherapy in clinical practice.