Photoaffinity Labeling-Based Chemoproteomic Strategy Reveals RBBP4 as a Cellular Target of Protopanaxadiol against Colorectal Cancer Cells

Fang Fang Zhuo; Qiang Guo; Yong Zhe Zheng; Ting Ting Liu; Zhuo Yang; Qi He Xu; Yong Jiang; Dan Liu; Ke Wu Zeng; Peng Fei Tu

doi:10.1002/cbic.202200038

Photoaffinity Labeling-Based Chemoproteomic Strategy Reveals RBBP4 as a Cellular Target of Protopanaxadiol against Colorectal Cancer Cells

Fang Fang Zhuo, Qiang Guo, Yong Zhe Zheng, Ting Ting Liu, Zhuo Yang, Qi He Xu, Yong Jiang, Dan Liu, Ke Wu Zeng^*, Peng Fei Tu

^*Corresponding author for this work

Inflammation Biology

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

2 Citations (Scopus)

Abstract

Protopanaxadiol (PPD), a main ginseng metabolite, exerts powerful anticancer effects against multiple types of cancer; however, its cellular targets remain elusive. Here, we synthesized a cell-permeable PPD probe via introducing a bifunctional alkyne-containing diazirine photo-crosslinker and performed a photoaffinity labeling-based chemoproteomic study. We identified retinoblastoma binding protein 4 (RBBP4), a chromatin remodeling factor, as an essential cellular target of PPD in HCT116 colorectal cancer cells. PPD significantly decreased RBBP4-dependent trimethylation at lysine 27 of histone H3 (H3K27me3), a crucial epigenetic marker that correlates with histologic signs of colorectal cancer aggressiveness, and PPD inhibition of proliferation and migration of HCT116 cells was antagonized by RBBP4 RNA silencing. Collectively, our study highlights a previously undisclosed anti-colorectal cancer cellular target of the ginseng metabolite and advances the fundamental understanding of RBBP4 functions via a chemical biology strategy.

Original language	English
Article number	e202200038
Journal	ChemBioChem
Volume	23
Issue number	13
DOIs	https://doi.org/10.1002/cbic.202200038
Publication status	Published - 5 Jul 2022

Keywords

chemoproteomics
colorectal cancer
medicinal chemistry
pharmacological target
protopanaxadiol

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10.1002/cbic.202200038

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title = "Photoaffinity Labeling-Based Chemoproteomic Strategy Reveals RBBP4 as a Cellular Target of Protopanaxadiol against Colorectal Cancer Cells",

abstract = "Protopanaxadiol (PPD), a main ginseng metabolite, exerts powerful anticancer effects against multiple types of cancer; however, its cellular targets remain elusive. Here, we synthesized a cell-permeable PPD probe via introducing a bifunctional alkyne-containing diazirine photo-crosslinker and performed a photoaffinity labeling-based chemoproteomic study. We identified retinoblastoma binding protein 4 (RBBP4), a chromatin remodeling factor, as an essential cellular target of PPD in HCT116 colorectal cancer cells. PPD significantly decreased RBBP4-dependent trimethylation at lysine 27 of histone H3 (H3K27me3), a crucial epigenetic marker that correlates with histologic signs of colorectal cancer aggressiveness, and PPD inhibition of proliferation and migration of HCT116 cells was antagonized by RBBP4 RNA silencing. Collectively, our study highlights a previously undisclosed anti-colorectal cancer cellular target of the ginseng metabolite and advances the fundamental understanding of RBBP4 functions via a chemical biology strategy.",

keywords = "chemoproteomics, colorectal cancer, medicinal chemistry, pharmacological target, protopanaxadiol",

author = "Zhuo, {Fang Fang} and Qiang Guo and Zheng, {Yong Zhe} and Liu, {Ting Ting} and Zhuo Yang and Xu, {Qi He} and Yong Jiang and Dan Liu and Zeng, {Ke Wu} and Tu, {Peng Fei}",

note = "Funding Information: This work was financial supported by National Key Technology R&D Program “New Drug Innovation” of China (grant no. 2019YFC1711000 and 2019YFC1708902), Shandong Scientific and Technological Innovation Major Project (grant no. 2019JZZY020905), and National Natural Science Foundation of China (NSFC) projects (grant no. 81973505). Publisher Copyright: {\textcopyright} 2022 Wiley-VCH GmbH.",

year = "2022",

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doi = "10.1002/cbic.202200038",

language = "English",

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T1 - Photoaffinity Labeling-Based Chemoproteomic Strategy Reveals RBBP4 as a Cellular Target of Protopanaxadiol against Colorectal Cancer Cells

AU - Zhuo, Fang Fang

AU - Guo, Qiang

AU - Zheng, Yong Zhe

AU - Liu, Ting Ting

AU - Yang, Zhuo

AU - Xu, Qi He

AU - Jiang, Yong

AU - Liu, Dan

AU - Zeng, Ke Wu

AU - Tu, Peng Fei

N1 - Funding Information: This work was financial supported by National Key Technology R&D Program “New Drug Innovation” of China (grant no. 2019YFC1711000 and 2019YFC1708902), Shandong Scientific and Technological Innovation Major Project (grant no. 2019JZZY020905), and National Natural Science Foundation of China (NSFC) projects (grant no. 81973505). Publisher Copyright: © 2022 Wiley-VCH GmbH.

PY - 2022/7/5

Y1 - 2022/7/5

N2 - Protopanaxadiol (PPD), a main ginseng metabolite, exerts powerful anticancer effects against multiple types of cancer; however, its cellular targets remain elusive. Here, we synthesized a cell-permeable PPD probe via introducing a bifunctional alkyne-containing diazirine photo-crosslinker and performed a photoaffinity labeling-based chemoproteomic study. We identified retinoblastoma binding protein 4 (RBBP4), a chromatin remodeling factor, as an essential cellular target of PPD in HCT116 colorectal cancer cells. PPD significantly decreased RBBP4-dependent trimethylation at lysine 27 of histone H3 (H3K27me3), a crucial epigenetic marker that correlates with histologic signs of colorectal cancer aggressiveness, and PPD inhibition of proliferation and migration of HCT116 cells was antagonized by RBBP4 RNA silencing. Collectively, our study highlights a previously undisclosed anti-colorectal cancer cellular target of the ginseng metabolite and advances the fundamental understanding of RBBP4 functions via a chemical biology strategy.

AB - Protopanaxadiol (PPD), a main ginseng metabolite, exerts powerful anticancer effects against multiple types of cancer; however, its cellular targets remain elusive. Here, we synthesized a cell-permeable PPD probe via introducing a bifunctional alkyne-containing diazirine photo-crosslinker and performed a photoaffinity labeling-based chemoproteomic study. We identified retinoblastoma binding protein 4 (RBBP4), a chromatin remodeling factor, as an essential cellular target of PPD in HCT116 colorectal cancer cells. PPD significantly decreased RBBP4-dependent trimethylation at lysine 27 of histone H3 (H3K27me3), a crucial epigenetic marker that correlates with histologic signs of colorectal cancer aggressiveness, and PPD inhibition of proliferation and migration of HCT116 cells was antagonized by RBBP4 RNA silencing. Collectively, our study highlights a previously undisclosed anti-colorectal cancer cellular target of the ginseng metabolite and advances the fundamental understanding of RBBP4 functions via a chemical biology strategy.

KW - chemoproteomics

KW - colorectal cancer

KW - medicinal chemistry

KW - pharmacological target

KW - protopanaxadiol

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ER -

Photoaffinity Labeling-Based Chemoproteomic Strategy Reveals RBBP4 as a Cellular Target of Protopanaxadiol against Colorectal Cancer Cells

Abstract

Keywords

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