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

Hiroki Miura; Kang Hsin Wang; Tomoki Inagaki; Frank Chuang; Michiko Shimoda; Chie Izumiya; Tadashi Watanabe; Ryan R. Davis; Clifford G. Tepper; Somayeh Komaki; Ken ichi Nakajima; Ashish Kumar; Yoshihiro Izumiya

doi:10.1016/j.chembiol.2024.10.003

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

Hiroki Miura, Kang Hsin Wang, Tomoki Inagaki, Frank Chuang, Michiko Shimoda, Chie Izumiya, Tadashi Watanabe, Ryan R. Davis, Clifford G. Tepper, Somayeh Komaki, Ken ichi Nakajima, Ashish Kumar, Yoshihiro Izumiya

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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 (K_D) 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.

Original language	English
Pages (from-to)	1909-1925.e7
Journal	Cell Chemical Biology
Volume	31
Issue number	11
DOIs	https://doi.org/10.1016/j.chembiol.2024.10.003
Publication status	Published - 21-11-2024
Externally published	Yes

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2024.10.003

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@article{3ff1ac55df93490985ef0eb373398b1a,

title = "A LANA peptide inhibits tumor growth by inducing CHD4 protein cleavage and triggers cell death",

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 = "cancer, cell differentiation, CHD4, KSHV, LANA, leukemia, peptide",

author = "Hiroki Miura and Wang, \{Kang Hsin\} and Tomoki Inagaki and Frank Chuang and Michiko Shimoda and Chie Izumiya and Tadashi Watanabe and Davis, \{Ryan R.\} and Tepper, \{Clifford G.\} and Somayeh Komaki and Nakajima, \{Ken ichi\} and Ashish Kumar and Yoshihiro Izumiya",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = nov,

day = "21",

doi = "10.1016/j.chembiol.2024.10.003",

language = "English",

volume = "31",

pages = "1909--1925.e7",

journal = "Cell Chemical Biology",

issn = "2451-9456",

publisher = "Elsevier Inc.",

number = "11",

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TY - JOUR

T1 - A LANA peptide inhibits tumor growth by inducing CHD4 protein cleavage and triggers cell death

AU - Miura, Hiroki

AU - Wang, Kang Hsin

AU - Inagaki, Tomoki

AU - Chuang, Frank

AU - Shimoda, Michiko

AU - Izumiya, Chie

AU - Watanabe, Tadashi

AU - Davis, Ryan R.

AU - Tepper, Clifford G.

AU - Komaki, Somayeh

AU - Nakajima, Ken ichi

AU - Kumar, Ashish

AU - Izumiya, Yoshihiro

PY - 2024/11/21

Y1 - 2024/11/21

N2 - 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.

AB - 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.

KW - cancer

KW - cell differentiation

KW - CHD4

KW - KSHV

KW - LANA

KW - leukemia

KW - peptide

UR - https://www.scopus.com/pages/publications/85209348018

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U2 - 10.1016/j.chembiol.2024.10.003

DO - 10.1016/j.chembiol.2024.10.003

M3 - Article

C2 - 39488208

AN - SCOPUS:85209348018

SN - 2451-9456

VL - 31

SP - 1909-1925.e7

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 11

ER -

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

Abstract

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