Biology subjects

Hagenbeek, T. J.

Publications and source records attributed to Hagenbeek, T. J..

3 recordsLinked to original sources

bioRxiv2025

Promoter-centric gene regulation in drug-resistant cancer

In eukaryotic cells, gene-distal regulatory elements (REs) facilitate long-range gene regulation, ensuring cell type-specific transcriptional programs. This mechanism is frequently disrupted in cancer, often driven by transcription factors (TFs) that serve as targets for cancer therapy. However, targeting these TFs can lead to acquired resistance mechanisms that are not fully understood. We demonstrate that mesothelioma cancer cells, dependent on the oncogenic driver TF family TEAD, develop resistance to a pan-TEAD inhibitor and revert to an evolutionarily ancient, promoter-centric gene regulatory mechanism to recover gene expression following TEAD inhibition. Base-pair-resolution 3D chromatin conformation mapping reveals that RE-promoter interactions are disrupted in resistant cells, despite epigenetic and transcriptomic recovery. Mechanistically, in resistant cells, TF complexes, including resistance-specific FOSL1 and KLF4, preferentially bind and enhance promoter activity to recover gene expression, rendering distal REs dispensable. Our findings highlight promoter elements and promoter-specific TFs as potential therapeutic targets using a model of drug-resistant cancer.

cancer biology↗

bioRxiv2024

TEAD-targeting small molecules induce a cofactor switch to regulate the Hippo pathway

TEAD proteins are the main transcriptional effectors of the Hippo signaling pathway and a pharmacological target in oncology. Most TEAD-targeting small molecules act by disrupting interaction with the oncogenic transcriptional activators YAP and TAZ. Here, we describe an alternative mechanism for TEAD lipid pocket binding molecules. We report that select sulfonamide-containing compounds promote TEAD interaction with the transcriptional repressor VGLL4 to induce a small molecule-mediated cofactor switch from YAP to VGLL4. Chemically induced VGLL4-TEAD complexes counteract YAP activity at chromatin to repress pro-growth gene networks, including genes involved in cellular proliferation and mechanosignaling. VGLL4 is required for an anti-proliferative response to these select compounds, and genetic deletion of VGLL4 causes resistance to these molecules in vitro and in vivo. Our data reveal a category of molecules that facilitate the repressive VGLL4-TEAD interaction and open up new understandings for curbing the oncogenic activity of Hippo pathway deregulation.

cancer biology↗

bioRxiv2023

Targeting the Hippo pathway in cancers via ubiquitination dependent TEAD degradation

The Hippo pathway is among the most frequently altered key signaling pathways in cancer. TEAD1-4 are essential transcription factors and key downstream effectors in the Hippo pathway in human cells. Here, we identified RNF146 as a ubiquitin ligase (E3) of TEADs, which negatively regulates their stability in cells through proteasome-mediated degradation. We show that RNF146-mediated TEAD ubiquitination is dependent on the TEAD PARylation state. We further validated the genetic interaction between RNF146 and the Hippo pathway in cancer cell lines and the model organism Drosophila melanogaster. Despite the RNF146 and proteasome-mediated degradation mechanisms, TEADs are stable proteins with a long half-life in cells. We demonstrate that degradation of TEADs can be greatly enhanced pharmacologically with heterobifunctional chemical inducers of protein degradation (CIDEs). These TEAD-CIDEs can effectively suppress activation of YAP/TAZ target genes in a dose-dependent manner and exhibit significant anti-proliferative effects in YAP/TAZ-dependent tumor cells, thus phenocopying the effect of genetic ablation of TEAD protein. Collectively, this study demonstrates that the ubiquitin-proteasome system plays an important role in regulating TEAD functions and provides a proof-of-concept demonstration that pharmacologically induced TEAD ubiquitination could be leveraged to target YAP/TAZ-driven cancers.

cancer biology↗