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

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 perfor...

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Published in:Chembiochem : a European journal of chemical biology 2022-07, Vol.23 (13), p.e202200038-n/a
Main Authors: Zhuo, Fang‐Fang, Guo, Qiang, Zheng, Yong‐Zhe, Liu, Ting‐Ting, Yang, Zhuo, Xu, Qi‐He, Jiang, Yong, Liu, Dan, Zeng, Ke‐Wu, Tu, Peng‐Fei
Format: Article
Language:English
Subjects:
Alkynes
Anticancer properties
Cancer
Cell migration
Cell proliferation
chemoproteomics
Chromatin remodeling
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Epigenetics
Ginseng
HCT116 Cells
Histone H3
Histones
Humans
Labeling
Lysine
medicinal chemistry
Metabolites
Methylation
Panax - chemistry
pharmacological target
Photoaffinity labeling
protopanaxadiol
Retina
Retinoblastoma
Retinoblastoma-Binding Protein 4 - genetics
Retinoblastoma-Binding Protein 4 - metabolism
RNA-mediated interference
Sapogenins - pharmacology
Transcription Factors - metabolism
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Summary: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. HCT116 cells were treated with the cell permeable probe AD‐PPD, and irradiated with UV in situ. Labelled proteomes were further conjugated to biotin‐PEG3‐azide via click chemistry, and the target of protopanaxadiol (PPD) was identified as RBBP4 by LC‐MS/MS analysis.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.202200038