Cannabinoids Transmogrify Cancer Metabolic Phenotype via Epigenetic Reprogramming and a Novel CBD Biased G Protein-Coupled Receptor Signaling Platform

SIMPLE SUMMARY: The epigenome is dynamic and flexible and can influence its phenotype by turning the genes on and off based on the environment to which it is exposed. Significant epigenetic changes detected are DNA methylation, histone modifications, and RNA-associated alterations. These modifications are potentially heritable across the genome, leading to transgenerational inheritance, and they can even be reversible based on lifestyle modifications. This review focuses on the environmental impact of cannabinoid factors and the subsequent combined effects on epigenetic modifications, such as cancer metabolism, through a biased G protein-coupled receptor signaling paradigm regulating several hallmarks of cancer. ABSTRACT: The concept of epigenetic reprogramming predicts long-term functional health effects. This reprogramming can be activated by exogenous or endogenous insults, leading to altered healthy and different disease states. The exogenous or endogenous changes that involve developing a roadmap of epigenetic networking, such as drug components on epigenetic imprinting and restoring epigenome patterns laid down during embryonic development, are paramount to establishing youthful cell type and health. This epigenetic landscape is considered one of the hallmarks of cancer. The initiation and progression of cancer are considered to involve epigenetic abnormalities and genetic alterations. Cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer development, including DNA methylation, histone modifications, nucleosome positioning, non-coding RNAs, and microRNA expression. Endocannabinoids are natural lipid molecules whose levels are regulated by specific biosynthetic and degradative enzymes. They bind to and activate two primary cannabinoid receptors, type 1 (CB1) and type 2 (CB2), and together with their metabolizing enzymes, form the endocannabinoid system. This review focuses on the role of cannabinoid receptors CB1 and CB2 signaling in activating numerous receptor tyrosine kinases and Toll-like receptors in the induction of epigenetic landscape alterations in cancer cells, which might transmogrify cancer metabolism and epigenetic reprogramming to a metastatic phenotype. Strategies applied from conception could represent an innovative epigenetic target for preventing and treating human cancer. Here, we describe novel cannabinoid-biased G protein-coupled receptor signaling platforms (GPCR), highlighting putative future perspectives in this field.