Transglutaminase 2-Mediated Histone H3Q5 Serotonylation: A Selective Epigenetic Regulator Driving Cell Proliferation and Migration in Colorectal Cancer

Colorectal carcinoma (CRC), a prevalent digestive malignancy and the second foremost cause of cancer fatalities globally. A recent discovery highlights a novel histone modification: serotonylation at histone H3Q5 (H3Q5ser), catalyzed by transglutaminase 2 (TG2). Although present in specific tissues like the colon, its epigenetic function in CRC remains elusive. Our research reveals increased TG2 and H3Q5ser levels in poorly-differentiated colorectal cancers. Furthermore, TG2 depletion in CRC cell lines hindered both cell growth and migration. We identified FOSL1 as a pivotal mediator within the TG2-regulated network, tightly linked to TG2 expression. Subsequently, TG2 influences the expression of MEK/ERK pathway targets indirectly via FOSL1. Epigenetic investigations shed light on the functional role of TG2-catalyzed H3Q5ser in regulating the transcription of genes implicated in cell proliferation and migration. TG2 extends H3Q5 serotonylation to the gene body and fortifies H3K4me3, thereby releasing RNA polymerase II from its paused state. Thus, our study suggests that TG2-mediated H3Q5ser significantly serves as a selective regulator, promoting the transcription of genes driving cell proliferation and migration by facilitating the release of paused RNA polymerase II, unveiling potential therapeutic targets for CRC.