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A LANA peptide inhibits tumor growth by inducing CHD4 protein cleavage and triggers cell death

Hiroki Miura1, Kang-Hsin Wang1, Tomoki Inagaki1

  • 1Department of Dermatology, School of Medicine, University of California Davis (UC Davis), Sacramento, CA 95817, USA.

Cell Chemical Biology
|November 2, 2024
PubMed

Insights

A novel peptide, VGN73, derived from Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA), inhibits chromodomain-helicase-DNA-binding protein 4 (CHD4). This peptide promotes cell differentiation and induces cancer cell death, offering potential for new therapies.

Area of Science:

  • Molecular Virology
  • Cell Biology
  • Cancer Therapeutics

Background:

  • Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency, with viral genes poised for transcription in latent chromatin.
  • KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4), inhibiting viral promoter activation.
  • CHD4 regulates cell differentiation by preventing enhancer-promoter activation.

Purpose of the Study:

  • To identify a peptide inhibitor of the LANA-CHD4 interaction.
  • To investigate the therapeutic potential of the identified peptide in cancer treatment.

Main Methods:

  • Identification of a LANA-derived peptide (VGN73) targeting the LANA-CHD4 interaction surface.
  • Characterization of VGN73 binding to CHD4 using dissociation constant (KD) measurements.
  • Assessment of VGN73 effects on monocyte differentiation (U937 cells) and gene expression.
  • Evaluation of VGN73-induced cell death, CHD4 cleavage, and tumor growth inhibition in a xenograft mouse model.

Main Results:

  • A peptide (VGN73) was identified that binds CHD4 with high affinity (KD = 14 nM).
  • VGN73 enhanced monocyte differentiation into macrophages and altered gene expression profiles.
  • In cancer cells, VGN73 induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in vivo.

Conclusions:

  • The LANA-derived peptide VGN73 acts as a CHD4 inhibitor.
  • VGN73 demonstrates potential as a therapeutic agent by promoting cell differentiation and inducing cancer cell death.
  • VGN73 may facilitate novel cell differentiation-based cancer therapies.
Keywords:
CHD4KSHVLANAapoptosisautophagycancercell differentiationleukemiamonocytepeptide

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