Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition

Frontiers in Oncology

Oncology

John Heckel¹  Gerbenn Seraphin¹  Vanessa McGaughey¹  Sandra Rieger²  Thomas S. Lisse³  Enrico Capobianco⁴ 

[1] Department of Biology, University of Miami, Coral Gables, FL, United States;Department of Biology, University of Miami, Coral Gables, FL, United States;Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States;Department of Biology, University of Miami, Coral Gables, FL, United States;Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States;iCURA DX, Malvern, PA, United States;The Jackson Laboratory, Farmington, CT, United States;

关键词: osteosarcoma;    vitamin D;    VDR;    ROS;    EMT;    Snai2;    metastasis;    cancer;   

DOI  :  10.3389/fonc.2023.1188641

 received in 2023-03-17, accepted in 2023-04-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti-cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on NMD-ROS-EMT signaling in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH)2D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand-bound VDR directly downregulated the EMT inducer SNAI2, differentiating highly metastatic from low metastatic subtypes and 1,25(OH)2D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDR’s integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients.

【 授权许可】

Unknown   
Copyright © 2023 Capobianco, McGaughey, Seraphin, Heckel, Rieger and Lisse