The functional role of a novel FOXM1/MYH10 protein complex in embryonic stem cells and cancer stem-like cells

Abstract

The regulation of self-renewal in stem cells is maintained by promotion of proliferation and inhibition of differentiation, which holds the key answer to the process of ageing and the origin of cancer. In order to investigate the pertinent roles of ageing factors in human embryonic stem (ES) cell self-renewal, FOXM1, FOXO3A and SIRT1 were selected as baits for protein binding partners. From our study, we identified the novel endogenous protein interaction of FOXM1 with MYH10. We confirmed that blebbistatin, a chemical inhibitor of MYH10, can improve human ES cell survival and prevent differentiation with a poor outcome for colony formation in a dosage dependent manner, which is mediated through FOXM1 via inducing BCL-2 protein level and enhancing promoter binding of OCT4, respectively. The inhibitions of FOXM1 and MYH10 showed abnormality of both centriole locations and key regulators of mitosis, suggesting the essential roles of FOXM1 and MYH10 in cell-cycle progression in respect to stem cell self-renewal. Genetic knockdown of FOXM1 and MYH10 revealed the essential requirement of these two proteins in pluripotency maintenance as well as a distinctive role for MYH10 in the integrity of stem cell colony. By applying our findings to CD44high/CD24low breast cancer stem-like cells, we found that FOXM1 and MYH10 are also major players in cancer stem-like cell maintenance. In terms of self-renewing ability, inhibition of MYH10 shows improved spheroid formation ability in MCF breast cancer stem-like cells associated with Rho/ROCK pathway. This inhibition of MYH10 in turn is dependent on the tissue origin of the breast cancer compared with its isoform. In conclusion, our findings of the protein complex of FOXM1 and MYH10 contributes to the understanding of the stem cell self-renewing mechanisms in both human embryonic and cancer stem-like cell models.