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

TY - JOUR

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

UR - http://www.scopus.com/inward/record.url?scp=85129299953&partnerID=8YFLogxK

U2 - 10.1002/cbic.202200038

DO - 10.1002/cbic.202200038

M3 - Article

C2 - 35442561

AN - SCOPUS:85129299953

SN - 1439-4227

VL - 23

JO - ChemBioChem

JF - ChemBioChem

IS - 13

M1 - e202200038

ER -