Abstract
Abstract We generated induced cancer stem cells that initiate osteosarcoma (OS) by overexpression of c-MYC and loss of Ink4a/Arf in bone marrow-derived stromal cells, and found that the loss of adipogenic potential is an essential event for OS tumorigenesis. Therefore, our understanding of regulatory mechanisms of adipocyte differentiateon would greatly contribute to control OS tumorigenesis. Here, we show that regulation of the transcriptional coactivator MKL1 (megakaryoblastic leukemia 1) by actin cytoskeleton dynamics drives adipocyte differentiation mediated by PPARγ. Exposure of preadipocytes to an adipogenic cocktail results in the rapid disruption of actin stress fibres as a consequence of downregulation of RhoA-ROCK signaling, which regulates the formation of actin stress fibers and focal adhesions, and the consequent increase in monomeric G-actin levels. The resulting increase in the amount of G-actin leads to the interaction of G-actin with MKL1, which prevents nuclear translocation of MKL1 and allows expression of PPARγ followed by adipogenic differentiation. We further found that depletion of MKL1 can drive adipocyte differentiation in preadipocytes and even in nonadipogenic fibroblasts in the absence of an adipogenic cocktail, and these data revealed that MKL1 functions as a gatekeeper that controls adipocyte differentiation. In addition, we found that treatment with ROCK inhibitors induced terminal adipocyte differentiateon even in OS stem cells through regulation of MKL1 by actin cytoskeleton dynamics, which resulted in a significant suppression of tumorigenesis. Our findings provide new insight into the regulatory mechanism of adipogenesis, and trans-differentiation approach by controlling actin cytoskeleton dynamics may provide a novel therapeutic strategy for targeting cancer stem cells. Citation Format: Hiroyuki Nobusue, Nobuhiro Takahashi, Nobuyuki Onishi, Takatsune Shimizu, Eiji Sugihara, Yoshinao Oki, Koichi Akashi, Koichiro Kano, Hideyuki Saya. Therapeutic strategies for osteosarcoma stem cells by regulating adipocyte differentiation based on actin dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1531. doi:10.1158/1538-7445.AM2017-1531
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
