Hiraki, MasayukiMaeda, TakahiroBouillez, AudreyAlam, MaroofTagde, AshujitHinohara, KunihikoSuzuki, YozoMarkert, TahirehMiyo, MasaakiKomura, KazumasaAhmad, RehanRajabi, HasanKufe, Donald2017-06-152016Hiraki, M., T. Maeda, A. Bouillez, M. Alam, A. Tagde, K. Hinohara, Y. Suzuki, et al. 2016. “MUC1-C ACTIVATES BMI1 IN HUMAN CANCER CELLS.” Oncogene 36 (20): 2791-2801. doi:10.1038/onc.2016.439. http://dx.doi.org/10.1038/onc.2016.439.http://nrs.harvard.edu/urn-3:HUL.InstRepos:33029814BMI1 is a component of the PRC1 complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16INK4a expression. In support of these results, analysis of three gene expresssion datasets demonstrated highly significant correlations between MUC1-C and BMI1 in breast cancers. These findings uncover a previously unrecognized role for MUC1-C in driving BMI1 expression and in directly interacting with this stem cell factor, linking MUC1-C with function of the PRC1 in epigenetic gene silencing.en-USMUC1-CBMI1PRC1H2AHOXC5HOXC13p16Journal Article2017-06-1510.1038/onc.2016.439