PVT1 interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma

• Published in: Haematologica (Roma) 2024-02, Vol.109 (2), p.567-577
• Main Authors: Nylund, Patrick, Garrido-Zabala, Berta, Párraga, Alba Atienza, Vasquez, Louella, Pyl, Paul Theodor, Harinck, George Mickhael, Ma, Anqi, Jin, Jian, Öberg, Fredrik, Kalushkova, Antonia, Wiklund, Helena Jernberg
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein - genetics; Genomics; Humans; Intracellular Signaling Peptides and Proteins; Multiple Myeloma - drug therapy; Plasma Cell DIsorders; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; RNA, Long Noncoding - genetics
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/HAEMATOL.2023.282965

Multiple myeloma is a heterogeneous hematological disease that originates from the bone marrow and is characterized by the monoclonal expansion of malignant plasma cells. Despite novel therapies, multiple myeloma remains clinically challenging. A common feature among patients with poor prognosis is the increased activity of the epigenetic silencer EZH2, which is the catalytic subunit of the PRC2. Interestingly, the recruitment of PRC2 lacks sequence specificity and, to date, the molecular mechanisms that define which genomic locations are destined for PRC2-mediated silencing remain unknown. The presence of a long non-coding RNA (lncRNA)-binding pocket on EZH2 suggests that lncRNA could potentially mediate PRC2 recruitment to specific genomic regions. Here, we coupled RNA immunoprecipitation sequencing, RNA-sequencing and chromatin immunoprecipitation-sequencing analysis of human multiple myeloma primary cells and cell lines to identify potential lncRNA partners to EZH2. We found that the lncRNA plasmacytoma variant translocation 1 (PVT1) directly interacts with EZH2 and is overexpressed in patients with a poor prognosis. Moreover, genes predicted to be targets of PVT1 exhibited H3K27me3 enrichment and were associated with pro-apoptotic and tumor suppressor functions. In fact, PVT1 inhibition independently promotes the expression of the PRC2 target genes ZBTB7C, RNF144A and CCDC136. Altogether, our work suggests that PVT1 is an interacting partner in PRC2-mediated silencing of tumor suppressor and pro-apoptotic genes in multiple myeloma, making it a highly interesting potential therapeutic target.