Histone methyltransferase KMT2D mediated lipid metabolism via peroxisome proliferator-activated receptor gamma in prostate cancer

作者：Zhai, Qiliang; Luo, Mayao; Zhang, Yifan; Zhang, Wenqiang; Wu, Chenwei; Lv, Shidong^*; Wei, Qiang^*

来源：Translational Cancer Research, 2022, 11(8): 2607-+.

DOI：10.21037/tcr-22-431

• Prostate cancer (PCa)
• kinase tethers histone-lysine N-methyltransferase 2D (KMT2D)
• peroxisome proliferator-activated receptor gamma (PPAR?)
• lipid metabolism
• rosiglitazone (ROSI)

Background: Prostate cancer (PCa) is the most common type of cancer in men. Destruction of or blocking lipid metabolism impairs the growth, proliferation, and survival of tumor cells. Recent studies on hepatic steatosis suggest that kinase tethers histone-lysine N-methyltransferase 2D (KMT2D) to peroxisome proliferator-activated receptor gamma (PPAR gamma), transactivating its target genes. Here, to determine a therapeutic approach that may interfere with PCa lipid metabolism, the interaction mechanism of KMT2D and PPAR gamma was verified in PCa. Methods: Molecular techniques and bioinformatics analysis were used to explore the relationship between KMT2D and lipid metabolism pathways in PCa. Moreover, the changes of lipid droplets were detected by oil red O staining and BODIPY staining. Molecular techniques were used to investigate the effect of KMT2D on PPAR gamma signaling in PCa cells. Co-immunoprecipitation (Co-IP) and DNA pull-down verified the mechanism of interaction between KMT2D and PPAR gamma. Results: KMT2D knockdown reduced the lipid droplet content in PC-3 and DU-14 5 cells and downregulated the expression of lipid metabolic genes. Low-dose rosiglitazone (ROSI) effectively activated the PPAR gamma pathway to promote lipid droplet synthesis and cell proliferation and migration. However, ROSI could not function effectively after KMT2D knockdown. Both co-IP and DNA pull-down analyses showed that KMT2D and PPAR gamma could be tethered to regulate the expression of PPAR gamma target genes. Conclusions: In PCa, KMT2D interacted with PPAR gamma, which directly participated in the regulation of lipid metabolism-related genes and affected lipid synthesis. Therefore, inhibiting the interaction between KMT2D and PPAR gamma is a potential therapeutic strategy.

• 单位
  南方医科大学; 南昌大学