Epigenetics Involvement in Oxaliplatin-Induced Potassium Channel Transcriptional Downregulation and Hypersensitivity.

Abstract

Peripheral neuropathy is the most frequent dose-limiting adverse effect of oxaliplatin. Acute pain symptoms that are induced or exacerbated by cold occur in almost all patients immediately following the first infusions. Evidence has shown that oxaliplatin causes ion channel expression modulations in dorsal root ganglia neurons, which are thought to contribute to peripheral hypersensitivity. Most dysregulated genes encode ion channels involved in cold and mechanical perception, noteworthy members of a sub-group of potassium channels of the K2P family, TREK and TRAAK. Downregulation of these K2P channels has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. We investigated the molecular mechanisms underlying this peripheral dysregulation in a murine model of neuropathic pain triggered by a single oxaliplatin administration. We found that oxaliplatin-mediated TREK-TRAAK downregulation, as well as downregulation of other K+ channels of the K2P and Kv families, involves a transcription factor known as the neuron-restrictive silencer factor (NRSF) and its epigenetic co-repressors histone deacetylases (HDACs). NRSF knockdown was able to prevent most of these K+ channel mRNA downregulation in mice dorsal root ganglion neurons as well as oxaliplatin-induced acute cold and mechanical hypersensitivity. Interestingly, pharmacological inhibition of class I HDAC reproduces the antinociceptive effects of NRSF knockdown and leads to an increased K+ channel expression in oxaliplatin-treated mice.

• Authors: Vanessa Pereira, Sylvain Lamoine, Mélissa Cuménal, Stéphane Lolignier, Youssef Aissouni, Anne Pizzoccaro, Laetitia Prival, David Balayssac, Alain Eschalier, Emmanuel Bourinet, Jérôme Busserolles
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 58 Issue 7 Pg. 3575-3587 (Jul 2021) ISSN: 1559-1182 [Electronic] United States
• PMID: 33772465 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Kcnk4 protein, mouse
• Potassium Channels
• Potassium Channels, Tandem Pore Domain
• RE1-silencing transcription factor
• Repressor Proteins
• potassium channel protein TREK-1
• Oxaliplatin

Topics

• Animals
• Antineoplastic Agents (toxicity)
• Down-Regulation (drug effects, physiology)
• Epigenesis, Genetic (drug effects, physiology)
• Hyperalgesia (chemically induced, genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Oxaliplatin (toxicity)
• Potassium Channels (biosynthesis, genetics)
• Potassium Channels, Tandem Pore Domain (biosynthesis, genetics)
• Repressor Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Transcription, Genetic (drug effects, physiology)