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-κB 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.
Highlights
Mucin 1 (MUC1) is a cell membrane heterodimeric complex that is aberrantly expressed in primary multiple myeloma (MM) cells and MM cell lines [1,2,3,4,5]
In extending these observations to primary MM cells from 2 patients with refractory disease, we found that targeting MUC1 C-terminal (MUC1-C) significantly reduces BMI1 levels (Figure 1C, left and right; Supplementary Figure 1C)
In concert with these results, the enforced overexpression of MUC1-C in OPM-2 cells was associated with an increase in BMI1 expression (Figure 1E, left and right), clearly indicating that MUC1-C and not the shed MUC1-N subunit is responsible for driving BMI1 expression
Summary
Mucin 1 (MUC1) is a cell membrane heterodimeric complex that is aberrantly expressed in primary multiple myeloma (MM) cells and MM cell lines [1,2,3,4,5]. The transmembrane MUC1 C-terminal (MUC1-C) subunit of the heterodimer functions as an oncoprotein that is necessary for the proliferation and survival of MM cells [5,6,7,8]. In this respect, the MUC1-C cytoplasmic domain is an intrinsically disordered 72-amino acid structure that has the plasticity to act as a node and intersect with multiple signaling pathways linked to self-renewal, inflammation and transformation [9, 10]. A cell-penetrating peptide, designated GO-203, has been developed that targets the MUC1-C CQC motif, inhibits MUC1-C homodimerization, nuclear import and function, and is effective in inducing MM cell death [6,7,8]
Sign-in/Register to view highlights & summary 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.
