Long Noncoding RNA PVT1 Is Regulated by Bromodomain Protein BRD4 in Multiple Myeloma and Is Associated with Disease Progression

Abstract

Long noncoding RNAs (lncRNAs) are deregulated in human cancers and are associated with disease progression. <i>Plasmacytoma Variant Translocation 1</i> (<i>PVT1)</i>, a lncRNA, is located adjacent to the gene <i>MYC</i>, which has been linked to multiple myeloma (MM). <i>PVT1</i> is expressed in MM and is associated with carcinogenesis. However, its role and regulation remain uncertain. We examined <i>PVT1</i>/<i>MYC</i> expression using real-time PCR in plasma cells purified from 59 monoclonal gammopathy of undetermined significance (MGUS) and 140 MM patients. The MM cell lines KMS11, KMS12PE, OPM2, and RPMI8226 were treated with JQ1, an <i>MYC</i> super-enhancer inhibitor, or MYC inhibitor 10058-F4. The expression levels of <i>PVT1</i> and <i>MYC</i> were significantly higher in MM than in MGUS (<i>p</i> < 0.0001) and were positively correlated with disease progression (<i>r</i> = 0.394, <i>p</i> < 0.0001). JQ1 inhibited cell proliferation and decreased the expression levels of <i>MYC</i> and <i>PVT1</i>. However, 10054-F4 did not alter the expression level of <i>PVT1</i>. The positive correlation between <i>MYC</i> and <i>PVT1</i> in patients, the synchronous downregulation of <i>MYC</i> and <i>PVT1</i> by JQ1, and the lack of effect of the <i>MYC</i> inhibitor on <i>PVT1</i> expression suggest that the expression of these two genes is co-regulated by a super-enhancer. Cooperative effects between these two genes may contribute to MM pathogenesis and progression.