DNMT3a contributes to the development and maintenance of bone cancer pain by silencing Kv1.2 expression in spinal cord dorsal horn

Metastatic bone tumor-induced changes in gene transcription and translation in pain-related regions of the nervous system may participate in the development and maintenance of bone cancer pain. Epigenetic modifications including DNA methylation regulate gene transcription. Here we report that intrathecal injection of decitabine, a DNA methyltransferase inhibitor, dose-dependently attenuated the development and maintenance of bone cancer pain induced by injecting prostate cancer cells (PCC) into the tibia. The level of the de novo DNA methyltransferase DNMT3a, but not DNMT3b, time-dependently increased in the ipsilateral L4/5 dorsal horn (not L4/5 dorsal root ganglion) after PCC injection. Blocking this increase through microinjection of recombinant adeno-associated virus 5 (AAV5) expressing Dnmt3a shRNA into dorsal horn rescued PCC-induced downregulation of dorsal horn Kv1.2 expression and impaired PCC-induced pain hypersensitivity. In turn, mimicking this increase through microinjection of AAV5 expressing full-length Dnmt3a into dorsal horn reduced dorsal horn Kv1.2 expression and produced pain hypersensitivity in the absence of PCC injection. Administration of neither decitabine nor virus affected locomotor function and acute responses to mechanical, thermal, or cold stimuli. Given that Dnmt3a mRNA is co-expressed with Kcna2 mRNA (encoding Kv1.2) in individual dorsal horn neurons, our findings suggest that the increased dorsal horn DNMT3a contributes to bone cancer pain through silencing dorsal horn Kv1.2 expression. DNMT3a may represent a potential new target for cancer pain management.