Figure 7. Targeting the MUC1-C → PRC1 pathway derepresses PTEN, p14ARF and BIM.

A. Lysates from the designated RPMI8226 (left) and OPM-2 (right) cells expressing a CshRNA or MUC1shRNA were immunoblotted with the indicated antibodies. B.-D. RPMI8226/CshRNA and RPMI8226/MUC1shRNA cells were analyzed for PTEN (B), p14^ARF (C) and BIM (D) mRNA levels by qRT-PCR (left). The results (mean±SD of 3 determinations) are expressed as relative mRNA levels as compared with that obtained for the CshRNA cells (assigned a value of 1). Lysates were immunoblotted with the indicated antibodies (right). E. Schema depicting the proposed involvement of MUC1-C in driving expression of the PRC1 components, BMI1, RING2 and RING1. MUC1-C activates the MYC gene in MM cells [8]. In turn, MYC occupies the BMI1 promoter by a MUC1-C-dependent mechanism and induces BMI1 expression. Targeting MUC1-C and thereby MYC also resulted in the downregulation of RING2, supporting a similar pathway for the regulation of BMI1 and RING2. MUC1-C binds directly to NF-κB p65 and promotes activation of NF-κB p65-target genes, including MUC1 itself in an autoinductive circuit [12]. Along these lines, targeting MUC1-C and NF-κB p65 resulted in the suppression of RING1 expression, indicating that MUC1-C regulates these three PRC1 components by a least two pathways. In contrast to BMI1 and RING2, targeting MYC was also associated with partial downregulation of RING1. In concert with the involvement of MUC1-C in regulating PRC1 components, the results further support a model in which MUC1-C activates PRC1 function and thereby the upregulation of H2AUb1 levels and suppression of PTEN, p14^ARF and BIM expression in MM cells.