CANT1 lncRNA triggers efficient therapeutic efficacy by correcting aberrant lncing cascade...

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CANT1 lncRNA triggers efficient therapeutic efficacy by correcting aberrant lncing cascade in malignant uveal melanoma

Molecular Therapy;February 25 2017: /DOI: 10.1016/j.ymthe.2017.02.016

Yue Xing, Xuyang Wen, Xia Ding, Jiayan Fan, Peiwei Chai, Renbing Jia, Shengfang Ge, Guanxiang Qian, He Zhang, Xianqun Fan

Abstract

Uveal melanoma (UM) is an intraocular malignant tumor with high mortality rate.Recent studies have shown the functions of long non-coding RNAs (lncRNAs) in tumorigenesis, thus, targeting tumor-specific lncRNA abnormalities has become an attractive approach for developing therapeutics to treat uveal melanoma. In this study, we identified a novel nuclear CANT1 lncRNA (CASC15-New-Transcript 1) and acts as a necessary UM suppressor. CANT1 significantly reduced the tumor metastatic capacity and tumor formation, either in cell culture or in animals harboring tumor xenograft. Intriguingly, XIST lncRNA serves as a potential target of CANT1, and JPX or FTX lncRNA subsequently plays a contextual hinge to activate a novel CANT1-JPX/FTX-XIST long non-coding (lncing) pathway in UM. Moreover, CANT1 triggers the expression of JPX or FTX by directly binding to their promoters and promoting H3K4 methylation. These observations delineate a novel lncing cascade in which lncRNAs directly build a long non-coding cascade without coding genes that aims to modulate UM tumorigenesis, thereby specifying a novel lncing-cascade renewal anti-tumor therapeutic strategy by correcting aberrant lncing cascade in uveal melanoma.

Introduction

Uveal melanoma (UM) is a special type of melanoma that originates in the uvea of the eyes and is the most common intraocular malignant tumor in adults. In the past decade, most studies have focused on the mechanisms underlying UM tumorigenesis by identifying chromosomal and/or genomic abnormalities. For instance, the loss of one copy of chromosome 3 has been identified as the most frequent event in UM. As early events, some mutations in GNAQ or GNA11 result in a marked promotion of cell proliferation and sensitize cells to mitogen-activated protein kinase (MAPK) inhibitors. In addition, it has been reported that the mutations found in BAP1 are strongly associated with increased metastasis. In contrast, mutations in SF3B1 or EIF1AX have been associated with good prognosis. Theoretically, the tumorigenesis is a multistep process involving genetic and epigenetic alterations. We thus were interested to shed light on the epigenetic mechanisms underlying UM progression

Epigenetics refers to the study of physiological traits that are inherited by daughter cells without changes in the DNA sequence. Epigenetic research mainly includes the regulation of non-coding RNAs, the modification of histone methylation, and conformational changes in the chromosomes. An increasing number of studies in various fields have particularly focused on the function of long non-coding RNAs (lncRNAs). For example, we previously reported that the Kcnq1ot1 lncRNA regulates Kcnq1 imprinting by orchestrating a long-range intrachromosomal loop. The RoR lncRNA can modulate pluripotency and self-renewal in iPSC induction [9]. Recent findings have also implicated lncRNAs in several of the steps leading to cancer development. For instance, the MALAT1 lncRNA is a highly conserved lncRNA that participates in tumor proliferation, migration and invasion in many common cancers. We recently also showed that ROR lncRNA blocks the binding of histone methyltransferase G9A to its target gene and promotes tumorigenesis. Thus, the orchestrating roles of lncRNA raise the hypothesis that correction of lncRNA-guided abnormalities has become an attractive strategy in control the malignancy of uveal melanoma.

Empire Genomic's XIST FISH Probe was used in this publication.

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