Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells

Sabrina Fischer; Van Tuan Trinh; Clara Simon; Lisa M Weber; Ignasi Forné; Andrea Nist; Gert Bange; Frank Abendroth; Thorsten Stiewe; Wieland Steinchen; Robert Liefke; Olalla Vázquez

doi:10.1016/j.chembiol.2023.05.012

Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells

Cell Chem Biol. 2023 Jul 20;30(7):766-779.e11. doi: 10.1016/j.chembiol.2023.05.012. Epub 2023 Jun 23.

Authors

Affiliations

¹ Institute of Molecular Biology and Tumor Research (IMT), University of Marburg, 35043 Marburg, Germany.
² Department of Chemistry, University of Marburg, 35043 Marburg, Germany.
³ Protein Analysis Unit, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-University (LMU) Munich, 82152 Martinsried, Germany.
⁴ Genomics Core Facility, Institute of Molecular Oncology, Member of the German Center for Lung Research (DZL), University of Marburg, 35043 Marburg, Germany.
⁵ Department of Chemistry, University of Marburg, 35043 Marburg, Germany; Center for Synthetic Microbiology (SYNMIKRO), University of Marburg, 35043 Marburg, Germany.
⁶ Institute of Molecular Biology and Tumor Research (IMT), University of Marburg, 35043 Marburg, Germany; Department of Hematology, Oncology, and Immunology, University Hospital Giessen and Marburg, 35043 Marburg, Germany. Electronic address: robert.liefke@imt.uni-marburg.de.
⁷ Department of Chemistry, University of Marburg, 35043 Marburg, Germany; Center for Synthetic Microbiology (SYNMIKRO), University of Marburg, 35043 Marburg, Germany. Electronic address: olalla.vazquez@staff.uni-marburg.de.

PMID: 37354906
DOI: 10.1016/j.chembiol.2023.05.012

Abstract

Inhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to perturb their biological functions. The Elongin BC heterodimer (ELOB/C) binds to a BC-box motif and is essential for cancer cell growth. Here, we report a peptide that mimics the high-affinity BC-box of the PRC2-associated protein EPOP. This peptide tightly binds to the ELOB/C dimer (k_D = 0.46 ± 0.02 nM) and blocks the association of ELOB/C with its interaction partners, both in vitro and in the cellular environment. Cancer cells treated with our peptide inhibitor showed decreased cell viability, increased apoptosis, and perturbed gene expression. Therefore, our work proposes that blocking the BC-box-binding pocket of ELOB/C is a feasible strategy to impair its function and inhibit cancer cell growth. Our peptide inhibitor promises novel mechanistic insights into the biological function of the ELOB/C dimer and offers a starting point for therapeutics linked to ELOB/C dysfunction.

Keywords: EPOP; Elongin BC; VHL; apoptosis; cancer; peptide inhibition; proliferation; protein-protein interactions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Elongin / metabolism
Neoplasms* / drug therapy
Peptides / metabolism
Peptides / pharmacology
Protein Binding
Transcription Factors* / metabolism
Ubiquitin-Protein Ligases / metabolism

Substances

Elongin
Transcription Factors
Peptides
Ubiquitin-Protein Ligases