Oncotarget

Priority Research Papers:

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

Ashujit Tagde, Tahireh Markert, Hasan Rajabi, Masayuki Hiraki, Maroof Alam, Audrey Bouillez, David Avigan, Kenneth Anderson and Donald Kufe _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:69237-69249. https://doi.org/10.18632/oncotarget.20144

Metrics: PDF 1605 views  |   HTML 3508 views  |   ?  


Abstract

Ashujit Tagde1,*, Tahireh Markert1,*, Hasan Rajabi1, Masayuki Hiraki1, Maroof Alam1, Audrey Bouillez1, David Avigan1, Kenneth Anderson1 and Donald Kufe1

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 20144