Polycomb Target Genes Are Silenced in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

Maternal dietary protein affects transcriptional regulation of myostatin gene distinctively at weaning and finishing stages in skeletal muscle of Meishan pigs

“…H3K27me3 is usually associated with transcriptional repression. 19 However, in the present study, the increase of H3K27me3 on MSTN promoter correlated with higher MSTN mRNA expression. Recently, advances in the study of chromatin modifications revealed the functional significance of cross-talk among modifications.…”

“…18,19 However, the same histone modification may exert different effects on gene transcription under different circumstances, depending on genomic location, tissue/cell types or developmental stages. For instance, H3K9me3 is a key repressive marker associated with gene silencing, but it can also be associated with transcriptional activation.…”

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

“…In multiple myeloma, it has been shown that PRC2 target genes are most often found silenced in myeloma (15). Exploration of EZH2 inhibitors in multiple myeloma models is therefore an attractive field of research which may lead to a broader understanding of multiple myeloma biology and will guide the development of new targeted therapies.…”

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

“…[14][15][16][17][18] EZH2 is expressed in undifferentiated stem-like cancer cells and promotes cancer cell proliferation and metastasis formation by repressing several tumor suppressor genes. 15,[19][20][21][22][23][24] Notably, its molecular or pharmacological inhibition leads to the reversal of the malignant phenotype.…”