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    • In the present study we did not examine

    2020-09-07

    In the present study, we did not examine whether the CpG site-specific COMT methylation are associated with any genetic variants in response to E2, GEN or SFN. Some studies suggest that oxidative DNA damage causes genetic variation which may induce epigenetic changes that lead to gene silencing (Khobta et al., 2010; Leng et al., 2012). Future studies on both epigenetic and genetic variations within the COMT promoters, especially in large human cohort studies may help to reveal the mechanisms underlying gene regulation of COMT and improve the use of COMT epigenetic/genetic variants for the assessment of BCa risk. On the other hand, our study is limited to an ER positive BCa cell line, MCF-7. It has been shown that an ER-antagonist, ICI182780, could reverse the reduction of COMT expression in MCF-7 Sunitinib Malate (Ho et al., 2013), indicating ER may mediate E2-induced COMT suppression. Future studies using several human BCa cells or clinical samples with known ER status might yield further insight on the influence of ERs on epigenetic regulation of COMT. Taken together, we provide new evidence of targeting COMT transcription epigenetically in MCF-7 cells. We identified a new mechanism which consists of locus specific DNA methylation and higher chromatin configurations at MB-COMT distal promoter, contributes to E2- or GEN-induced COMT suppression. Furthermore, we indicated that SFN might serve as an epigenetic modifier to modulate the estrogens-induction of aberrant epigenetic changes of genes involved in estrogen metabolism. All in all, our findings may help in improving our understanding of factors involved in estrogen metabolism in human BCa.
    Conflict of interest
    Acknowledgments This work was partly supported by National Institutes of Health (ES016887-Wan Yee Tang), National Natural Science Foundation of China, China (81728018-Wan Yee Tang) and Natural Science Foundation of Jiangsu Province, China (BK20161571-Qian Wu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declared they have no potential competing financial interests.
    Introduction Cognitive deficits are widely acknowledged as core features of schizophrenia: they are detectable in over 80% of patients, precede the onset of psychosis by many years and continue to worsen despite antipsychotic treatments, leading to functional disability (Kahn and Keefe, 2013). A better understanding of the mechanisms underlying the cognitive impairment is thus of extreme relevance. On the one hand, it would increase knowledge on the etiopathogenesis of the disease, since cognitive deficits may be considered as indicators of vulnerability and endophenotypes. On the other hand, it may allow to identify new targets for selective pharmacological treatments, as well as key features for rehabilitation programs. For these reasons, cognition has been, and still is, a focus of research in schizophrenia and several genetic and environmental factors, as well as their interaction, have been reported to affect cognitive performance (Bosia et al., 2015). Interestingly, some of these factors have been firstly explored for their role in the development of psychosis and later a stronger link with cognition emerged. In particular, the interaction between Catechol-O-Methyltransferase (COMT) gene and cannabis use has gained increasing attention in the past years. Cannabis use is exceedingly common ((Bahorik et al., 2014) 8%) and overwhelming evidence suggests that, especially during adolescence, it represents a major risk factor for psychosis (Gage et al., 2016), associated with earlier onset and more pronounced symptoms (Arseneault et al., 2002, 2004). Moreover, delta-9-tetrahydrocannabinol (THC), the main active compound in cannabis, can induce transient psychotic-like experiences (D\'Souza et al., 2004). Animal and human studies further indicate that acute exposure to exogenous cannabinoids indirectly activates D2 receptors and dopaminergic transmission in the striatum and mesolimbic areas, while prolonged exposure results in a reduction of the dopamine in the prefrontal cortex (Maria Pelayo-Teran et al., 2012), thus providing a biological rationale for the clinical and epidemiological data. In line with this, an interaction model with COMT genetic variation has been proposed. The COMT gene, initially investigated for its possible role in the susceptibility for the disease, is one of the most extensively examined gene in the neurocognition of schizophrenia (Barnes et al., 2006; Degenhardt and Hall, 2006). The COMT gene encodes an enzyme responsible for degrading the majority of prefrontal cortical dopamine. The COMT Val158Met functional polymorphism regulates the enzymatic activity, with the Val allele leading to increased prefrontal dopamine catabolism and thus lower extracellular dopamine levels (Bosia et al., 2015).