PAUPAR lncRNA suppresses tumourigenesis by H3K4 demethylation in uveal melanoma

Abstract

Edited by Tamas DalmayUveal melanoma (UM) is the most common primary intraocular tumour in adults and has a high incidence. Nearly 50% of patients with UM develop metastases after diagnosis. Long noncoding RNAs (lncRNAs) are involved in both oncogenic and tumour suppression pathways. We show that lncRNA PAUPAR is present at low levels in UM tissues and cell lines and modulates the tumourigenesis of UM in vitro and in vivo. The ectopic expression of PAUPAR in UM cells revealed that PAUPAR acts as a necessary UM suppressor and induces the silencing of HES1 expression, which significantly reduces tumour metastasis. Mechanistically, PAUPAR modulates HES1 expression by inhibiting histone H3K4 methylation. These data support a role of this lncRNA as a novel therapeutic target in cancer prevention and treatment.Keywords: H3K4 methylation; lncRNA PAUPAR; uveal melanoma Uveal melanoma (UM) is the most common primary intraocular tumour in adults, with an incidence of approximately 6-7 cases per million people per year [1]. Nearly 50% of patients with UM develop metastases within 10-15 years after diagnosis, most frequently in the liver [2], and the metastatic disease is universally fatal, with an average survival of 2-8 months [3]. Eighty per cent of metastatic patients die within 1 year and 92% within 2 years of diagnosis of metastasis [4], for which no effective systemic therapies are currently available [5]. UM arises in the pigmented cells of the eye, including the iris, ciliary body or choroid [6], differing from cutaneous melanoma (CM). Although CM and UM are both derived from melanocytes, they show remarkable differences in terms of tumourigenesis, the mode of metastatic spreading, genetic alterations and the therapeutic response [7]. Therefore, the molecular pathogenesis of UM is different from that of CM. Metastatic UM is the most feared complication of the disease and the main cause of death, and a systemic treatment is therefore urgently needed [8]. Furthermore, investigation of UM would be helpful to provide novel approaches for clinical therapy.The human transcriptome is more complex than a collection of protein-coding genes and their splice variants, showing extensive antisense, overlapping and noncoding RNA expression [9][10][11][12][13][14]. Epigenetic regulation includes regulation by noncoding RNA, modifications of the DNA methylation and histone Abbreviations

Functional characteristics of novel pancreatic Pax6 regulatory elements

“…Pauper was previously identified as a CNS-specific lncRNA expressed from the Pax6 locus that was able to bind multiple regulatory elements in cis and trans and linked to intraocular tumours (45,57). Using short hairpin RNA-mediated downregulation of Paupar, Vance et al (45) showed it could transcriptionally regulate Pax6 , whilst Pax6 knockdown did not affect Paupar levels, suggesting that the mechanism was not via a Pax6 autoregulatory affect.…”

Role of Epigenetics in Uveal Melanoma

“…Ding et al discovered that lncRNA PAUPAR acted as a necessary UM suppressor and could silence HES1 expression, which significantly reduced metastasis. Mechanistically, PAUPAR inhibits histone H3K4 methylation to modulate HES1 expression 37. Lei demonstrated that lncRNA MALAT1 was upregulated in the uveal melanoma tissues and cell lines.…”

“…In addition, transcription factor HES1 is overexpressed in UM cell lines and is associated with its metastatic capacity. And one of the reasons of upregulated expression of HES1 in UM cells is H3K4 trimethylation of the HES1 promoter 37.…”

Function and Clinical Implications of Long Non-Coding RNAs in Melanoma

“…The lncRNA PAX6 upstream antisense RNA (PAUPAR) was found in uveal melanoma tissues and uveal melanoma cell lines at low levels, suggesting that it might act as a tumor suppressor lncRNA [114]. Effectively it impacts tumorigenesis in vitro and in vivo by reducing tumor metastases significantly.…”

“…Effectively it impacts tumorigenesis in vitro and in vivo by reducing tumor metastases significantly. Further experiments showed that PAUPAR acts as a guide lncRNA by inducing the silencing of the transcription factor hairy and enhancer of split-1(HES1) by inhibiting histone H3K4 tri-methylation at the HES1 locus (Figure 1B and Table 1) [114]. …”