DNMT3a contributes to bone cancer pain by epigenetic silencing of Kcnq2/Kcnq3 in dorsal root ganglion neurons

Abstract

Metastatic bone tumors induce transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to bone cancer pain. A key factor in this process is the downregulation of Kv7 (KCNQ)/M channels in DRG neurons, leading to neuronal hyperexcitability and pain hypersensitivity. However, the mechanisms underlying bone cancer-induced Kv7 channels suppression remain poorly understood. DNA methyltransferase (DNMT)-mediated DNA methylation is known to suppress gene expression. In this study, we demonstrate that DNMT3a plays a critical role in the genesis of bone cancer pain, likely through the transcriptional repression of Kcnq2 and Kcnq3 genes. Furthermore, we identified C/EBPβ as a transcriptional activator of Dnmt3a, whose expression is upregulated in DRG neurons during bone cancer progression. Further studies suggest that VEGFA may be involved as an upstream signaling molecule in DNMT3a-mediated transcriptional repression of Kcnq2 and Kcnq3. Activation of the VEGFA/VEGFR2-PI3K-Akt-C/EBPβ signaling pathway correlates with DNMT3a-mediated transcriptional inhibition of Kcnq2/Kcnq3 genes in DRG neurons, which may lead to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. Collectively, these findings suggest that VEGFA/VEGFR2-PI3K-Akt-C/EBPβ signaling may represent a critical axis in DNMT3a-dependent epigenetic regulation of Kv7 (KCNQ)/M channels, offering potential therapeutic avenues for bone cancer pain management.

Perspective

This study reveals that VEGFA/VEGFR2-PI3K-Akt-C/EBPβ-DNMT3a axis drives bone cancer pain via epigenetic repression of Kcnq2/3 in DRG neurons, identifying promising therapeutic targets for cancer pain management.