LAUSR

Simple Summary From the landmark report of protein serotonylation on small GTPases in 2003 to the most recent discovery of serotonin-modified histone H3 leading to epigenetic changes, over the course of the past 20 years, there is still a cloud of mystery surrounding this rare post-translational modification, other than the fact that tissue transglutaminase, perhaps most famously known for its role in celiac disease, is the enzyme responsible for catalyzing this transamidation reaction. This review seeks to interpret the role of protein serotonylation in transcriptional regulation through some of the mechanistic and intertwining details of the modification, its potential modulation of the epigenetic landscape, as well as potential implications in lung and other types of cancer. Abstract In the case of small-cell lung carcinoma, the highly metastatic nature of the disease and the propensity for several chromatin modifiers to harbor mutations suggest that epigenetic manipulation may also be a promising route for oncotherapy, but histone deacetylase inhibitors on their own do not appear to be particularly effective, suggesting that there may be other regulatory parameters that dictate the effectiveness of vorinostat’s reversal of histone deacetylation. Recent discoveries that serotonylation of histone H3 alters the permissibility of gene expression have led to renewed attention to this rare modification, as facilitated by transglutaminase 2, and at the same time introduce new questions about whether this modification belongs to a part of the concerted cohort of regulator events for modulating the epigenetic landscape. This review explores the mechanistic details behind protein serotonylation and its possible connections to the epigenome via histone modifications and glycan interactions and attempts to elucidate the role of transglutaminase 2, such that optimizations to existing histone deacetylase inhibitor designs or combination therapies may be devised for lung and other types of cancer.