O-class forkhead box (FOXO) transcription factors are critical regulators of diverse cellular processes, including apoptosis, cellcycle arrest, DNA damage repair and oxidative stress resistance. Here, we show that FOXO1 and FOXO3a have an essential function in promoting cell detachment-induced anoikis, resistance to which is implicated in cancer development and metastasis. In contrast, the oncoprotein cyclin D1 inhibits anoikis. We further show that cyclin D1 interacts with FOXO proteins and impedes their transcriptional regulatory and anoikis-promoting functions. This effect of cyclin D1 requires its transcription repression domain but is independent of cyclin-dependent kinases CDK4 and CDK6. Moreover, we show that cancer-derived mutants of cyclin D1 are much more stable than wild-type cyclin D1 under anchorage-independent conditions and possess a greater antagonistic effect on FOXO-regulated anoikis and anchorage-independent growth of cancer cells. These data suggest that cyclin D1 may have a critical function in tumorigenesis and cancer metastasis by inhibiting the anoikis-promoting function of FOXO proteins.
Bibliographical noteFunding Information:
Acknowledgements. We thank DJ Tindall, KL Guan, M Pagano, CY Young, and SW Hayward for plasmids and cell lines, Y Shimizu, V Bardwell, KL Schwertfeger, SM Dehm and members of Huang laboratory, especially LR Bohrer for critical reading of the manuscript. This work was supported in part by funds from the Department of Defense (W81XWH-07-1-0137 and PC080591) and the Brainstorm Award from the University of Minnesota Masonic Cancer Center (to HH), the National Institutes of Health (CA82295 to JBM and CA099996 to KEK), and the National Natural Science Foundation of China (30500109 to LG). All authors claim no conflict of interest with this study.