KMT2B induces the H3K4 trimethylation of RBBP6 promoter to enhance the I sensitivity in thyroid carcinoma by restraining STAT1/DPP4 axis.

[BACKGROUND] Radioactive iodine (RAI) resistance severely limits treatment efficacy in thyroid carcinoma (THCA), yet its molecular underpinnings remain incompletely elucidated. In the present study, we sought to reveal the molecular mechanism by which histone lysine methyltransferase 2B (KMT2B) regulated dipeptidyl peptidase 4 (DPP4)-mediated THCA resistance to RAI.

[METHODS] Sequential Chromatin immunoprecipitation (ChIP)-re-ChIP assay was performed to evaluate the co-binding of KMT2B and H3K4 trimethylation (H3K4me3) at the retinoblastoma-binding protein 6 (RBBP6) promoter. Co-immunoprecipitation analyzed the STAT1 ubiquitination levels. Co-immunoprecipitation and GST pull-down analyzed the protein-protein interaction between RBBP6 and STAT1. STAT1 and DPP4 promoter binding were assessed via a ChIP assay.

[RESULTS] DPP4 was upregulated in 131I-resistant THCA cells. The knockdown of DPP4 inhibited the THCA cell resistance to RAI. STAT1 bound to the DPP4 promoter to enhance its transcription. RBBP6 facilitated the ubiquitinated degradation of STAT1 protein. Overexpression of DPP4 abrogated the THCA tumor-suppressive effects mediated by RBBP6 overexpression. KMT2B augmented the expression of RBBP6 through H3K4me3 modification. The inhibitory effects of KMT2B overexpression on proliferation, migration, and invasion of 131I-resistant THCA cells were counteracted by DPP4 overexpression.

[CONCLUSION] KMT2B enhanced RAI sensitivity in THCA via H3K4me3-mediated RBBP6 upregulation, driving STAT1 ubiquitination and degradation to suppress DPP4 transcription.