Comprehensive Analyses of SOX7 Provide Novel Insights on Its Tumor Suppressor Role and Its Target Genes with Therapeutic Implications in Multiple Myeloma
TL;DR
Results indicate that SOX7 functions as a tumor suppressor in MM, and its inactivation promotes cell cycle progression, and the anti-myeloma effects of panobinostat in MM.1S cells may be partially mediated through SOX7 induction.
Abstract
Multiple myeloma (MM) is an incurable hematological malignancy. SOX7, located within the recurrently deleted 8p23.1 region in MM, is suggested to act as a tumor suppressor. We characterized SOX7 through genetic, epigenetic, and functional analyses in MM cell lines. SOX7 was frequently silenced due to deletion and/or promoter hypermethylation. Ectopic SOX7 expression in KMS-18 and MM.1S cell lines caused a progressive decline in SOX7-transduced cells and induced G1 cell cycle arrest and/or apoptosis. Although SOX7 re-expression did not enhance bortezomib efficacy, treatment with the pan-histone deacetylase inhibitor panobinostat induced G1 arrest, promoted apoptosis, and increased SOX7 expression in MM.1S cells. Whole-transcriptome sequencing identified G1/S progression-related Wnt/β-catenin pathway genes as major SOX7-regulated targets, while ChIP-Seq analysis revealed widespread genomic SOX7 occupancy in MM.1S. Flow cytometric analysis of permeabilized bone marrow tumor cells from newly diagnosed and relapsed MM patients demonstrated generally low SOX7 protein expression. Collectively, these results indicate that SOX7 functions as a tumor suppressor in MM, and its inactivation promotes cell cycle progression. The anti-myeloma effects of panobinostat in MM.1S cells may be partially mediated through SOX7 induction.