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Updated: Oct 11, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
Published on: March 27, 2020
KSHV transactivator-derived small peptide traps coactivators to attenuate MYC and inhibits leukemia and lymphoma cell
Michiko Shimoda1,2, Yuanzhi Lyu3, Kang-Hsin Wang3
1Department of Dermatology, School of Medicine, University of California Davis (UC Davis), Sacramento, CA, USA. mshimoda@ucdavis.edu.
Abstract:
In herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors. Here, we show a small peptide derived from the Kaposi's sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular MYC expression, reduces cell proliferation, and selectively kills cancer cell lines in both tissue culture and a xenograft tumor mouse model. Mechanistically, the peptide functions as a decoy to block the recruitment of coactivator complexes consisting of Nuclear receptor coactivator 2 (NCOA2), p300, and SWI/SNF proteins to the MYC promoter in primary effusion lymphoma cells. Thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM seq) with target-transcriptional analyses further confirm that the viral peptide directly attenuates MYC and MYC-target gene expression. This study thus provides a unique tool to control MYC activation, which may be used as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases.
Insights
A novel peptide from a herpesvirus protein selectively kills cancer cells by blocking MYC gene activation. This discovery offers a potential new therapy for MYC-dependent cancers and autoimmune diseases.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Herpesvirus replication often suppresses host cell gene transcription by viral factors hijacking cellular machinery.
- The MYC gene is a critical regulator of cell proliferation and is frequently dysregulated in various cancers.
Purpose of the Study:
- To investigate a novel peptide derived from Kaposi's sarcoma-associated herpesvirus transactivator (K-Rta) as a potential therapeutic agent.
- To determine the mechanism by which this peptide affects MYC expression and cancer cell viability.
Main Methods:
- A synthetic peptide based on K-Rta was designed and tested in cancer cell lines and a xenograft mouse model.
- Mechanistic studies involved assessing coactivator complex recruitment to the MYC promoter using techniques like SLAM seq and transcriptional analyses.
Main Results:
- The K-Rta-derived peptide effectively reduced MYC expression and cell proliferation in cancer cell lines.
- The peptide selectively induced cancer cell death in vitro and in vivo.
- Mechanistically, the peptide acted as a decoy, preventing the assembly of essential coactivator complexes (NCOA2, p300, SWI/SNF) at the MYC promoter.
Conclusions:
- A K-Rta-derived peptide serves as a potent inhibitor of MYC transcription and a selective cancer cell killer.
- This peptide represents a promising therapeutic strategy for diseases driven by MYC activation, including cancers and autoimmune disorders.
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