Suppression of MKL1 promotes adipocytic differentiation and reduces the proliferation of myxoid liposarcoma cells

Abstract

Myxoid liposarcoma (MLS) is thought to occur due to defective adipocytic differentiation in mesenchymal stem cells. A promising strategy for MLS treatment is the prevention of sarcomagenesis by promoting the terminal differentiation of MLS cells into adipocytes. Previous studies have reported that the suppression of megakaryoblastic leukemia 1 (MKL1) expression induces adipocytic differentiation in preadipocyte cell lines. The present study aimed to investigate the effects of MKL1 suppression on MLS cells. In the present study, MKL1 knockdown was demonstrated to promote the adipocytic differentiation of an MLS-derived cell line, designated 1955/91, under adipogenic conditions. This suggests that therapeutic targeting of the MKL1-associated molecular pathway has potential as a promising method of MLS treatment. However, the induction of adipogenesis by MKL knockdown was incomplete, and Oil Red O staining indicated that intracellular lipid droplets were only sporadically generated. Conversely, MKL1 knockdown reduced the growth of the MLS cells. As adipocytic differentiation in vitro requires cellular confluence, the decreased growth rate of the MLS cells following MKL1 knockdown could be attributed to the incomplete induction of adipogenesis. Translocated in liposarcoma-CCAAT/enhancer-binding protein homologous protein (TLS-CHOP) is an MLS-specific oncoprotein that is thought to play key roles in sarcomagenesis and the suppression of adipocytic differentiation. However, the results of western blotting analyses suggest that TLS-CHOP has limited effects on MKL1 expression in MLS cells and that MKL1 knockdown hardly affects TLS-CHOP expression. Thus, it is postulated that the inhibitory effect of TLS-CHOP on adipogenesis is not associated with MKL1 expression. However, MKL1 and the molecular pathway involving MKL1 appear to be attractive targets for the differentiation therapy of MLS.

Keywords: MKL1; Oil Red O staining; adipocytic differentiation; differentiation therapy; myxoid liposarcoma.