The HDAC2-YY1 Complex Epigenetically Regulates Spinal Glutamate Transporter Activities: Implication For Therapeutic Target For Chemotherapy-induced Painful Peripheral Neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects of neurotoxic chemotherapy resulting in pain and decreased quality of life. Approximately 30 to 70% of patients receiving chemotherapy develop CIPN. Due to the lack of fully understanding of the mechanisms underlying CIPN, the current treatments are mainly empirical based on other neuropathic pain conditions rather than specifically targeting CIPN. Upregulation of histone deacetylase 2 (HDAC2) has been linked to impaired synaptic plasticity, which is well known to associate with the development of neuropathic pain. Here, we report that among the class I and II HDAC family, only HDAC2 was significantly upregulated in the spinal dorsal horn (SDH) of rat CIPN model following the long-lasting mechanical allodynia (over 28 days) induced by paclitaxel (cumulative does 8mg/kg, intraperitoneal injection). The enhanced expression of HDAC2 was mainly expressed in the spinal dorsal neurons but also observed in astrocytes. Both paclitaxel-induced mechanical allodynia and HDAC2 overexpression were inhibited by non-specific HDAC inhibitor valproic acid (VAP), HDAC2 inhibitor BRD6688, or knockdown HDAC2 by siRNA-HDAC2 (intrathecal injection). Notably, transcription factor Yin Yang 1 (YY1), a novel identified player in pain modulation, was found not only increased in expression but also co-expressed with HDAC2 in the superficial dorsal horn following paclitaxel treatment and mechanical allodynia occurred. The interaction between HDAC2 and YY1 in CIPN was confirmed by co-immunoprecipitation (Co-IP), and their interaction was suppressed by BRD6688 or knockdown HDAC2 using siRNA-HDAC2. In the same animals developing painful neuropathy after paclitaxel, glutamate level detected by Gas chromatography-mass spectrometry (GC-MS) was markedly increased whereas excitatory amino acid transporter 2 (EAAT2) was significantly decreased in SDH compared to that in the vehicle treated group. YY1 often recruits HDAC as co-repressor to suppress gene expression. In glial cells, excessive glutamate induced YY1 binding to EAAT promoters leading to decreased EAAT activity. The current findings indicate that YY1, via recruiting HDAC2, may form a HDAC2-YY1 complex during CIPN development to tip the balance between glutamate release and reuptake, leading to painful hypersensitivity. Blocking HDAC2-YY1 interaction may restore this balance and relieve the symptoms of CIPN.