Targeting MUC1-C suppresses polycomb repressive complex 1 in multiple myeloma

// Ashujit Tagde 1,* , Tahireh Markert 1,* , Hasan Rajabi 1 , Masayuki Hiraki 1 , Maroof Alam 1 , Audrey Bouillez 1 , David Avigan 1 , Kenneth Anderson 1 and Donald Kufe 1 1 Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Donald Kufe, email: // Keywords : MUC1-C, multiple myeloma, BMI1, RING1, RING2 Received : June 30, 2017 Accepted : July 16, 2017 Published : August 10, 2017 Abstract The polycomb repressive complex 1 (PRC1) includes the BMI1, RING1 and RING2 proteins. BMI1 is required for survival of multiple myeloma (MM) cells. The MUC1-C oncoprotein is aberrantly expressed by MM cells, activates MYC and is also necessary for MM cell survival. The present studies show that targeting MUC1-C with (i) stable and inducible silencing and CRISPR/Cas9 editing and (ii) the pharmacologic inhibitor GO-203, which blocks MUC1-C function, downregulates BMI1, RING1 and RING2 expression. The results demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism. MUC1-C thus promotes MYC occupancy on the BMI1 promoter and thereby activates BMI1 expression. We also show that the MUC1-C →MYC pathway induces RING2 expression. Moreover, in contrast to BMI1 and RING2, we found that MUC1-C drives RING1 by an NF-kB p65-dependent mechanism. Targeting MUC1-C and thereby the suppression of these key PRC1 proteins was associated with downregulation of the PRC1 E3 ligase activity as evidenced by decreases in ubiquitylation of histone H2A. Targeting MUC1-C also resulted in activation of the PRC1-repressed tumor suppressor genes, PTEN, CDNK2A and BIM . These findings identify a heretofore unrecognized role for MUC1-C in the epigenetic regulation of MM cells.