Suppression of Cancer Cell Stemness and Drug Resistance via MYC Destabilization by Deubiquitinase USP45 Inhibition with a Natural Small Molecule

SIMPLE SUMMARY: Cancer stem cells (CSCs) play significant roles in cancer development, drug resistance and cancer recurrence. Thus, it is of great importance to study and target the mechanism by which CSCs are regulated. On the basis of our investigations, we have discovered that USP45 as a new deubiquitinase of MYC significantly promoted cervical cancer development, stemness and drug resistance. Our findings have established the close connection among USP45, MYC and CSCs. Moreover, we have identified that USP45 can be specifically bound and inhibited by a natural small molecule (α-mangostin), in turn significantly suppressing the USP45-induced stemness and drug resistance of CSCs. On the basis of our USP45 discoveries, a new window has opened for suppressing CSCs development, stemness and drug resistance. Our exciting discovery will attract a broad audience in clinical CSCs target therapy, signaling pathways, natural products, drug discovery and drug development. ABSTRACT: Cancer stem cells (CSCs) play significant roles in cancer development, drug resistance and cancer recurrence. In cancer treatments based on the CSC characteristics and inducing factors, MYC is a promising target for therapeutic molecules. Although it has been regarded as an undrugable target, its stability tightly regulated by the ubiquitin–proteasome system offers a new direction for molecule targeting and cancer treatment. Herein we report our discoveries in this research area, and we have found that deubiquitinase USP45 can directly bind with MYC, resulting in its deubiquitination and stabilization. Further, USP45 overexpressing can upregulate MYC, and this overexpressing can significantly enhance cancer development, cancer cell stemness and drug resistance. Interestingly, without enhancing cancer development, MYC silencing with shRNA can only suppress USP45-induced stemness and drug resistance. Moreover, we have identified that USP45 can be specifically bound and inhibited by a natural small molecule (α-mangostin), in turn significantly suppressing USP45-induced stemness and drug resistance. Since USP45 is significantly expressed in cervical tumors, we have discovered that the combination of α-mangostin and doxorubicin can significantly inhibit USP45-induced cervical tumorigenesis in an animal model. In general, on the basis of our USP45 discoveries on its MYC deubiquitination and α-mangostin inhibition, suppressing USP45 has opened a new window for suppressing cancer development, stemness and drug resistance.