KMT2B promotes SHPRH expression to regulate ¹³¹I sensitivity in thyroid carcinoma cells by affecting FYN protein stability

Radioiodine (¹³¹I) is one of the most well-known and widely used targeted therapies. In thyroid carcinoma (THCA), it has been applied for more than eight decades and is still being utilized to eliminate remnants after resection and to reduce tumor metastases. Here, we aimed to investigate if lysine methyltransferase 2B (KMT2B) silencing could confer ¹³¹I resistance to THCA cells and the epigenetic mechanism behind. RT-qPCR, immunohistochemistry and western blot revealed that KMT2B was poorly expressed in THCA cells, and ¹³¹I resistance of cells led to a further decrease in KMT2B expression. EdU, colony formation, TUNEL, and tumor growth and metastasis assays showed that overexpression of KMT2B sensitized THCA cell to ¹³¹I and inhibited cell growth and metastasis. Further bioinformatics prediction and functional assay validation revealed that KMT2B elevated SHPRH expression via H3K4me3 modification in the SHPRH promoter, and that SHPRH modulated FYN ubiquitination, thereby promoting its protein degradation. We finally proved that the ¹³¹I-resistant cells regained resistance to ¹³¹I by FYN overexpression in the presence of KMT2B overexpression in vitro and in vivo. Therefore, we conclude that the overexpression of KMT2B represents a potential target for THCA therapy.