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

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 can-cer cell growth. Here, we report a peptide that mimics the high-affinity BC-box of the PRC2-associated pro-tein EPOP. This peptide tightly binds to the ELOB/C dimer (kD = 0.46 & PLUSMN; 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.