SETDB1 Modulates Degradation of Phosphorylated RB and Anticancer Efficacy of CDK4/6 Inhibitors

Retinoblastoma (RB) protein can exert tumor suppressor funcHowever, coadministration of the CDK4/6 inhibitor palbociclib tions even when it becomes phosphorylated. It is thus essential to blocked ASO-induced RB degradation and resulted in a much understand how phosphorylated RB (p-RB) expression and funcgreater cancer-inhibitory effect than each inhibitor alone both tion are regulated. Here, we demonstrated that RING finger domain in vitro and in vivo. This study identified CDK4/6-dependent, protein TRIM28 bound and promoted ubiquitination and degraTRIM28-mediated proteasomal degradation as a mechanism of RB dation of CDK4/6-phosphorylated RB protein. SETDB1, a known inactivation and reveals SETDB1 as a key inhibitor of this process. TRIM28 binding partner, protected p-RB from degradation Our findings suggest that combined targeting of SETDB1 and through the binding of methylated RB by its Tudor domain CDK4/6 represents a viable approach for the treatment of cancers independent of its methyltransferase activity. SETDB1 was found with SETDB1 gene amplification or overexpression. to be frequently overexpressed due to gene amplification and positively correlated with p-RB in prostate cancer patient speci-Significance: The identification of a role for TRIM28 and SETDB1 mens. Inhibition of SETDB1 expression using a gene-specific in regulating CDK4/6-phosphorylated RB stability uncovers a com-antisense oligonucleotide (ASO) reduced tumor growth but accelbination strategy using CDK4/6 and SETDB1 inhibition to decrease erated RB protein degradation, limiting the therapeutic efficacy. RB degradation and inhibit cancer growth.