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Phosphorylated RB represses the transcriptional activity of ETS1 to modulate the sensitivity of prostate cancer cells to CDK4/6 inhibitors [CUT&Tag]

ABSTRACT: CDK4/6 inhibitors are potential drugs for PCa treatment. Exploring underlying mechanism of cquired resistance to CDK4/6 inhibitors a is very important for the clinical application of these drugs. In the present study, we found that inhibiton of EGFR increased the sensitivity of PCa to CDK4/6 inhibitors in an RB-dependent manner. Mechanically, we demonstrate that the RB 249SPRT252 motif phosphorylated by CDK4/6 bound with ETS1 to transcriptionally decreased the expression of ZNF783, which inactivated the EGFR tyrosine kinase inhibitor resistance pathway. While, treatment with CDK4/6 inhibitors de-phosphorylated RB and diminished the interaction between RB and ETS1 to activated the EGFR tyrosine kinase inhibitor resistance pathway through enhancing the expression of ZNF783, which resulted in the acquired resistance of PCa to CDK4/6 inhibitors. Furthermore, we employed RB 249SPRT252 motif derived the phospho-mimic plasmid or PROTAC to verify the these findings. Collectively, this study not only revealed a new mechanism by which phosphorylated RB suppresses the transcriptionally function of ETS1 but also provided a novel strategy for enhancing the antitumor effect of CDK4/6 inhibitors on PCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266426 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:The retinoblastoma tumor suppressor protein (Rb) regulates early G1 phase checkpoints, including the DNA damage response, as well as cell cycle exit and differentiation. The widely accepted model of G1 cell cycle progression proposes that cyclin D:Cdk4/6 partially inactivates the Rb tumor suppressor during early G1 phase by progressive multi-phosphorylation, termed hypo-phosphorylation, resulting in release of E2F transcription factors. However, this model remains largely unproven biochemically and the biologically active form(s) of Rb remains unknown. Here we find that Rb is un-phosphorylated in G0 cells and becomes exclusively mono-phosphorylated throughout all of early G1 phase by cyclin D:Cdk4/6. Early G1 phase mono-phosphorylated Rb is composed of 14 independent isoforms that are all targeted by the E1a oncoprotein, but each shows a preferential binding pattern to specific E2F1-4 transcription factors. At the late G1 Restriction Point, cyclin E:Cdk2 inactivates Rb by a quantum hyper-phosphorylation (>12 phosphates/Rb). Cells undergoing a DNA damage response activate cyclin D:Cdk4/6 to generate mono-phosphorylated Rb that regulates global transcription. In contrast, a non-phosphorylatable ?Cdk-Rb allele was non-functional for regulating a DNA damage response, but functional for driving cell cycle exit and differentiation during myogenesis. These observations fundamentally change our understanding of G1 cell cycle progression and show that there is no progressive multi-phosphorylation or hypo-phosphorylation inactivation of Rb during early G1 phase by cyclin D:Cdk4/6. Instead, cyclin D:Cdk4/6 generates functionally active, mono-phosphorylated Rb that is the only Rb isoform present in cells during early G1 phase. Global transcriptional analysis of murine embryonic fibroblasts (MEFs) with conditional deletion of the endogenous RB gene by treatment with cell permeable TAT-Cre. Comparison to unaltered MEFs and MEFs with physiological level of exogenous wildtype or phospho-mutant RB expressed at time of RB gene deletion.

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Phosphorylated RB represses the transcriptional activity of ETS1 to modulate the sensitivity of prostate cancer cells to CDK4/6 inhibitors [CUT&Tag]

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