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Endocrine Abstracts (2019) 63 OC1.3 | DOI: 10.1530/endoabs.63.OC1.3

ECE2019 Oral Communications Calcium and Bone (5 abstracts)

Menin and EZH2 activities modulate the expression of the long non-coding RNA HAR1B in parathyroid tumors

Annamaria Morotti 1, , Chiara Verdelli 3 , Vito Guarnieri 4 , Lucia Anna Muscarella 5 , Rosa Silipigni 6 , Silvana Guerneri 6 , Leonardo Vicentini 7 , Valentina Vaira 1, & Sabrina Corbetta 8,


1Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; 2Division of Pathology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; 3Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 4Medical Genetics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy; 5Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy; 6Laboratory of Medical Genetics, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 7Endocrine Surgery, IRCCS Istituto Auxologico Italiano, Milan, Italy; 8Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 9Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.


Epigenetic deregulation is emerging as a component of the parathyroid tumorigenesis. We identified a long non-coding RNA (LNCRNA) signature clearly distinguishing parathyroid adenomas (PAds) and carcinomas from normal glands. Among the deregulated LncRNAS, HAR1B was upregulated in PAds harboring the common chromosome 11q loss of heterozygosity (Chr11q-LOH; n=10) compared with PAds harboring normal chromosome 11 haplotype (Chr11q-WT; n=12; P<0.0001), suggesting its involvement in Chr11q LOH-related parathyroid tumorigenesis. Considering the oncosuppressor MEN1 mapping on Chr11q, transient silencing of the MEN1 gene expression in PAds-derived cells (n=5) increased HAR1B expression levels. We tested the hypothesis that other genes mapping on Chr11q may be involved in HAR1B modulation: EED and DPF2 genes, whose proteins are components of the polycomb repressive complex 2 (PRC2) and BAF complex, respectively, map on Chr11q. Interestingly, the MEN1 product menin is known to cooperate with EZH2, the PRC2-methyltransferase, to repress a number of genes, and the HAR1B promoter is predicted to be regulated by EZH2. We investigated the role of EZH2 activity in this context: treatment with Tazemetostat, a selective inhibitor of EZH2 activity, increased the HAR1B expression levels in HEK293T cells. Notably, H3K27me3 protein levels, modulated by the EZH2 activity, were lower in Chr11q-LOH compared with Chr11q-WT PAds, and, analyzing the expression levels of the EZH2 target genes AXIN2, CCND1 and CDKN1A/p21 in the series of genotyped PAds, all transcripts significantly differed between Chr11q-LOH and Chr11q-WT PAds, suggesting the occurrence of reduced EZH2 activity in Chr11q-LOH PAds. Investigating the HAR1B functional role, we detected in HEK293T cells silenced for HAR1B, upregulation of LEF1 and WNT1 mRNA levels and a decrease in CDKN2B/p15 protein levels, while silencing of the HAR1B gene in PAds-derived cells (n=3) did not induce significant changes in the expression of the parathyroid specific genes CASR, VDR and GCM2, though a trend in PTH transcripts increase could be observed. Further experiments to investigate the function of HAR1B are ongoing. In conclusions, HAR1B emerges as a new candidate gene in Chr11q-LOH-related parathyroid tumorigenesis, likely as consequence of reduced menin and EZH2 repressive activity. Our data suggest a new function of menin as modulator of the LncRNAs expression.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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