1.Research progress in the mechanism of selenium supplement therapy for thyroid associated ophthalmopathy
Chinese Journal of Experimental Ophthalmology 2017;35(9):857-861
Thyroid associated ophthalmopathy (TAO) is an organ-specific autoimmune-inflammatory disorder,ranking top among the orbital diseases with highest incidences.TAO is characterized by a complex pathogenesis,including glycosaminoglycan and hyaluronic acid deposition,fibrosis of extraocular muscle and adipose degeneration of ocular tissue.The physical manifestations of the disease include periorbital edema,double vision,ophthalmoptosis,ocular dryness,eyelid retraction and on occasion vision loss secondary to optic nerve compression.Selenium evolves in the diversified pathogenesis of TAO.Although the therapeutic effects for TAO of selenium have already been proven,some problems appear to be no clear among the clinicians,such as its optimum dose,duration of the treatment,and safety to date,etc.Nowadays,the mechanism of selenium supplementation in TAO treatment includes neutralization of reactive oxygen,inhibition of HLA-DR expression,inhibition of secretion of TSHR-Ab and TPO-Ab.The aim of the review was to summarize the studies of selenium supplementation theray for TAO.
2.Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+synthesis by reprogramming H3K79 methylation in uveal melanoma
Xiang GU ; Yu HUA ; Jie YU ; Ludi YANG ; Shengfang GE ; Renbing JIA ; Peiwei CHAI ; Ai ZHUANG ; Xianqun FAN
Journal of Pharmaceutical Analysis 2023;13(1):24-38
Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1 L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1 L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accel-erator by enhancing nicotinamide adenine dinucleotide(NAD+)synthesis.Therapeutically,DOT1L inhi-bition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.
3.Novel insights into histone lysine methyltransferases in cancer therapy:From epigenetic regulation to selective drugs
Qili LIAO ; Jie YANG ; Shengfang GE ; Peiwei CHAI ; Jiayan FAN ; Renbing JIA
Journal of Pharmaceutical Analysis 2023;13(2):127-141
The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and im-mune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.