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. 2024 Nov 21;31(11):1909-1925.e7.
doi: 10.1016/j.chembiol.2024.10.003. Epub 2024 Nov 1.

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

Hiroki Miura  1 , Kang-Hsin Wang  1 , Tomoki Inagaki  1 , Frank Chuang  2 , Michiko Shimoda  1 , Chie Izumiya  1 , Tadashi Watanabe  3 , Ryan R Davis  4 , Clifford G Tepper  2 , Somayeh Komaki  1 , Ken-Ichi Nakajima  1 , Ashish Kumar  5 , Yoshihiro Izumiya  6
Affiliations

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

Hiroki Miura et al. Cell Chem Biol. .

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (KD) of 14 nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy.

Keywords: CHD4; KSHV; LANA; apoptosis; autophagy; cancer; cell differentiation; leukemia; monocyte; peptide.

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Conflict of interest statement

Declaration of interests H.M., K.-H.W., and Y.I. filed provisional patents related to the VGN73 peptides utilization for therapeutics purposes through University of California Davis. M.S. and Y.I. are founders of VGN Bio, Inc. and are planning to further develop VGN73 as therapeutics tools.

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