Inhibition of BMI-1 Induces Apoptosis through Downregulation of DUB3-Mediated Mcl-1 Stabilization

BMI-1, a polycomb ring finger oncogene, is highly expressed in various cancer cells and plays a critical role in cancer cell proliferation, invasion, and apoptosis. It serves as a cancer stemness marker associated with the regulation of stem cell self-renewal. In this study, pharmacological inhibition using PTC596 or knockdown using siRNA of BMI-1 reduced cancer stem-like cells and enhanced cancer cell death. These findings underscore the importance of BMI-1 in maintaining cancer stem cell populations and highlight its potential as a therapeutic target. The reduction in cancer stem-like cells and increased cancer cell death observed in this study suggest that targeting BMI-1 could disrupt the self-renewal capacity of cancer stem cells, thereby limiting tumor initiation and progression.

Mechanistically, the inhibition of BMI-1 led to the downregulation of the Mcl-1 protein without affecting Mcl-1 mRNA levels. PTC596 decreased Mcl-1 protein expression at the post-translational level through the proteasome-ubiquitin system. This suggests that BMI-1 may regulate Mcl-1 stability at the protein level, independent of transcriptional control. Both PTC596 and BMI-1 siRNA caused the downregulation of DUB3 deubiquitinase, which was strongly linked to Mcl-1 destabilization. Overexpression of Mcl-1 or DUB3 inhibited apoptosis induced by PTC596, indicating that the destabilization of Mcl-1 contributes to the pro-apoptotic effects of BMI-1 inhibition. These findings reveal a novel pathway by which BMI-1 contributes to cancer cell survival and suggest that disrupting this pathway could enhance the efficacy of cancer therapies.

Collectively, these findings demonstrate that the inhibition of BMI-1 induces Mcl-1 destabilization via downregulation of DUB3, ultimately leading to the induction of cancer cell death. This study provides mechanistic insights into how BMI-1 contributes to cancer cell survival and highlights the therapeutic potential of targeting BMI-1 in cancer treatment. The downregulation of DUB3 and subsequent destabilization of Mcl-1 represent a critical axis in the regulation of cancer cell survival, suggesting that inhibitors like PTC596 could be particularly effective in targeting cancer stem cells and promoting apoptosis. These results warrant further investigation into the clinical application of BMI-1 inhibitors as a novel strategy for cancer therapy.