Inhibition of FBP1 expression by KMT5A through TWIST1 methylation is one of the mechanisms leading to chemoresistance in breast cancer

Abstract

Abstract Purpose: Lysine methyltransferase 5A (KMT5A) is the sole mammalian enzyme known to catalyze the monomethylation of histone H4 lysine 20 and nonhistone proteins such as p53, which are involved in the occurrence and progression of many cancers. Our study aimed to determine the function of KMT5A in inducing docetaxel resistance in patients with breast carcinoma by evaluating glucose metabolism and the underlying mechanism involved. Methods: We examined the upregulation or downregulation of KMT5A-related proteins after KMT5A knockdown in breast cancer cells by Tandem Mass Tag proteomics. Through differential protein expression and pathway enrichment analysis, the upregulated key gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) was found. Loss of FBP1 expression is closely related to the development and prognosis of cancers. A dual-luciferase reporter gene assay confirmed that KMT5A inhibited the expression of FBP1 and that overexpression of FBP1 could enhance the chemotherapeutic sensitivity to docetaxel through the suppression of KMT5A expression. The KMT5A inhibitor UNC0379 was used to verify that docetaxel resistance induced by KMT5A through the inhibition of FBP1 depended on the methylase activity of KMT5A. According to previous literature and interaction network structure, we found that KMT5A acts on the transcription factor TWIST1. Then, we verified that TWSIT1 promoted the expression of FBP1 by using dual-luciferase reporter gene experiments. Conclusion: KMT5A affects chemotherapy resistance by regulating the cell cycle and positively regulates glycolysis-mediated chemotherapy resistance by inhibiting the transcription of FBP1 in collaboration with TWIST1. KMT5A may be a potential therapeutic target for chemotherapy resistance in breast cancer.