Abstract
Atypical chemokine receptor 3 (ACKR3) has emerged as a key player in various biological processes. Its atypical “intercepting receptor” properties have established ACKR3 as the major regulator in the pathophysiological processes in many diseases. In this study, we investigated the role of ACKR3 activation in promoting colorectal tumorigenesis. We showed that ACKR3 expression levels were significantly increased in human colon cancer tissues, and high levels of ACKR3 predicted the increased severity of cancer. In Villin-ACKR3 transgenic mice with a high expression level of CKR3 in their intestinal epithelial cells, administration of AOM/DSS induced more severe colorectal tumorigenesis than their WT littermates. Cancer cells of Villin-ACKR3 transgenic mice were characterised by the nuclear β-arrestin-1 (β-arr1)-activated perturbation of rRNA biogenesis. In HCT116 cells, cotreatment with CXCL12 and AMD3100 selectively activated ACKR3 and induced nuclear translocation of β-arr1, leading to an interaction of β-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). NOLC1, as the phosphorylated protein, further interacted with fibrillarin, a conserved nucleolar methyltransferase responsible for ribosomal RNA methylation in the nucleolus, thereby increasing the methylation in histone H2A and promoting rRNA transcription in ribosome biogenesis. In conclusion, ACKR3 promotes colorectal tumorigenesis through the perturbation of rRNA biogenesis by the β-arr1-induced interaction of NOLC1 with fibrillarin.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Huynh C, Dingemanse J, Schwabedissen HEM, Sidharta PN. Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions. Pharmacol Res. 2020;161:105092.
Stacer AC, Fenner J, Cavnar SP, Xiao A, Zhao S, Chang SL, et al. Endothelial CXCR7 regulates breast cancer metastasis. Oncogene. 2016;35:1716–24.
Bachelerie F, Graham GJ, Locati M, Mantovani A, Murphy PM, Nibbs R, et al. New nomenclature for atypical chemokine receptors. Nat Immunol. 2014;15:207–8.
Cancellieri C, Vacchini A, Locati M, Bonecchi R, Borroni EM. Atypical chemokine receptors: from silence to sound. Biochem Soc Trans. 2013;41:231–6.
Meyrath M, Szpakowska M, Zeiner J, Massotte L, Merz MP, Benkel T, et al. The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nat Commun. 2020;11:3033.
Luker KE, Lewin SA, Mihalko LA, Schmidt BT, Winkler JS, Coggins NL, et al. Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells. Oncogene. 2012;31:4750–8.
Sanchez-Martin L, Sanchez-Mateos P, Cabanas C. CXCR7 impact on CXCL12 biology and disease. Trends Mol Med. 2013;19:12–22.
Yan Y, Su J, Zhang Z. The CXCL12/CXCR4/ACKR3 response axis in chronic neurodegenerative disorders of the central nervous system: therapeutic target and biomarker. Cell Mol Neurobiol. 2021; https://doi.org/10.1007/s10571-021-01115-1.
Gutjahr JC, Crawford KS, Jensen DR, Naik P, Peterson FC, Samson GPB, et al. The dimeric form of CXCL12 binds to atypical chemokine receptor 1. Sci Signal. 2021;14:eabc9012.
Jiang C, Li R, Xiu C, Ma X, Hu H, Wei L, et al. Upregulating CXCR7 accelerates endothelial progenitor cell-mediated endothelial repair by activating Akt/Keap-1/Nrf2 signaling in diabetes mellitus. Stem Cell Res Ther. 2021;12:264.
Song S, Liu B, Habibie H, van den Bor J, Smit MJ, Gosens R, et al. D-dopachrome tautomerase contributes to lung epithelial repair via atypical chemokine receptor 3-dependent Akt signaling. EBioMedicine. 2021;68:103412.
Correia AL, Guimaraes JC, Auf der Maur P, De Silva D, Trefny MP, Okamoto R, et al. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature. 2021;594:566–71.
Giallongo C, Dulcamare I, Tibullo D, Del Fabro V, Vicario N, Parrinello N, et al. CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment. Oncogenesis. 2022;11:6.
Song ZY, Wang F, Cui SX, Gao ZH, Qu XJ. CXCR7/CXCR4 heterodimer-induced histone demethylation: a new mechanism of colorectal tumorigenesis. Oncogene. 2019;38:1560–75.
Scott MGE, Rouzic EL, Perianin A, Pierotti V, Enslen H, Benichou S, et al. Differential nucleocytoplasmic shuttling of beta-arrestins. Characterization of a leucine-rich nuclear export signal in beta-arrestin2. J Biol Chem. 2002;277:37693–701.
Meier UT. Comparison of the rat nucleolar protein Nopp140 with its Yeast Homolog SRP40. J Biol Chem. 1996;271:19376–84.
Kim YK, Jin Y, Vukoti KM, Park JK, Kim EE, Lee KJ, et al. Purification and characterization of human nucleolar phosphoprotein 140 expressed in Escherichia coli. Protein Expr Purif. 2003;31:260–4.
Yi Y, Li Y, Meng Q, Li Q, Li F, Lu B, et al. A PRC2-independent function for EZH2 in regulating rRNA 2’-O methylation and IRES-dependent translation. Nat Cell Biol. 2021;23:341–54.
Bryant CJ, McCool MA, Abriola L, Surovtseva YV, Baserga SJ. A high-throughput assay for directly monitoring nucleolar rRNA biogenesis. Open Biol. 2022;12:210305.
Zhang YH, Shi WN, Wu SH, Miao RR, Sun SY, Luo DD, et al. SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression. Oncogene. 2020;39:5214–27.
Deng QD, Lei XP, Zhong YH, Chen MS, Ke YY, Li Z, et al. Triptolide suppresses the growth and metastasis of non-small cell lung cancer by inhibiting β-catenin-mediated epithelial-mesenchymal transition. Acta Pharmacol Sin. 2021;42:1486–97.
Trerè D. AgNOR staining and quantification. Micron. 2000;31:127–31.
Pai CY, Chen HK, Sheu HL, Yeh NH. Cell-cycle-dependent alterations of a highly phosphorylated nucleolar protein p130 are associated with nucleologenesis. J Cell Sci. 1995;108:1911–20.
Duchemin A, O’Grady T, Hanache S, Mereau A, Thiry M, Wacheul L, et al. DHX15-independent roles for TFIP11 in U6 snRNA modification, U4/U6.U5 tri-snRNP assembly and pre-mRNA splicing fidelity. Nat Commun. 2021;12:6648.
Nguyen HT, Reyes-Alcaraz A, Yong HJ, Nguyen LP, Park HK, Inoue A, et al. CXCR7: a beta-arrestin-biased receptor that potentiates cell migration and recruits beta-arrestin2 exclusively through Gbetagamma subunits and GRK2. Cell Biosci. 2020;10:134.
Charest PG, Terrillon S, Bouvier M. Monitoring agonist-promoted conformational changes of beta-arrestin in living cells by intramolecular BRET. EMBO Rep. 2005;6:334–40.
Min K, Yoon HJ, Park JY, Baidya M, Dwivedi-Agnihotri H, Maharana J, et al. Crystal structure of beta-Arrestin 2 in complex with CXCR7 phosphopeptide. Structure. 2020;28:1014–23.
Becker JH, Gao Y, Soucheray M, Pulido I, Kikuchi E, Rodríguez ML, et al. CXCR7 reactivates ERK signaling to promote resistance to EGFR kinase inhibitors in NSCLC. Cancer Res. 2019;79:4439–52.
Lin L, Han MM, Wang F, Xu LL, Yu HX, Yang Y, et al. CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression. Cell Death Dis. 2014;5:e1488.
Wang P, Wu Y, Ge X, Ma L, Pei G. Subcellular localization of beta-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus. J Biol Chem. 2003;278:11648–53.
Hwang YC, Lu TY, Huang DY, Kuo YS, Kao CF, Yeh NH, et al. NOLC1, an enhancer of nasopharyngeal carcinoma progression, is essential for TP53 to regulate MDM2 expression. Am J Pathol. 2009;175:342–54.
Huang H, Li T, Chen M, Liu F, Wu H, Wang J, et al. Identification and validation of NOLC1 as a potential target for enhancing sensitivity in multidrug resistant non-small cell lung cancer cells. Cell Mol Biol Lett. 2018;23:54.
Yuan F, Zhang Y, Ma L, Cheng Q, Li G, Tong T, et al. Enhanced NOLC1 promotes cell senescence and represses hepatocellular carcinoma cell proliferation by disturbing the organization of nucleolus. Aging Cell. 2017;16:726–37.
Yuan F, Li G, Tong T. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) regulates the nucleolar retention of TRF2. Cell Death Discov. 2017;3:17043.
Penzo M, Montanaro L, Trere D, Derenzini M. The ribosome biogenesis-cancer connection. Cells. 2019;8:8010055.
Pelletier J, Thomas G, Volarević S. Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat Rev Cancer. 2018;18:51–63.
Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene. 2006;25:6384–91.
Grummt I. The nucleolus-guardian of cellular homeostasis and genome integrity. Chromosoma. 2013;122:487–97.
Boulon S, Westman BJ, Hutten S, Boisvert FM, Lamond AI. The nucleolus under stress. Mol Cell. 2010;40:216–27.
Meier UT. The many facets of H/ACA ribonucleoproteins. Chromosoma. 2005;114:1–14.
Hassouni BE, Sarkisjan D, Vos JC, Giovannetti E, Peters GJ. Targeting the ribosome biogenesis key molecule Fibrillarin to avoid chemoresistance. Curr Med Chem. 2019;26:6020–32.
Tessarz P, Santos-Rosa H, Robson SC, Sylvestersen KB, Nelson CJ, Nielsen ML, et al. Glutamine methylation in histone H2A is an RNA-polymerase-I-dedicated modification. Nature. 2014;505:564–8.
Acknowledgements
This work was supported by Beijing Natural Science Foundation (7212149/7222253) and National Natural Science Foundation of China (82173841/81872884/81973350/81772637/82002574).
Author information
Authors and Affiliations
Contributions
SXC conceived the project. JY, YNL and TP performed the experiments of molecular mechanisms and conducted animal studies. SHW provided clinical samples and pathological analysis. RRM performed statistical analysis. XJQ wrote the paper, which was edited by all authors.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Yang, J., Miao, Rr., Li, Yn. et al. Atypical chemokine receptor 3 induces colorectal tumorigenesis in mice by promoting β-arrestin-NOLC1-fibrillarin-dependent rRNA biogenesis. Acta Pharmacol Sin 43, 2967–2976 (2022). https://doi.org/10.1038/s41401-022-00901-x
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41401-022-00901-x
Keywords
This article is cited by
-
Fibrillarin and fibrillarin-like their role in cancer progression: new approaches and perspectives
Molecular Biology Reports (2026)
-
The role of physical activity and epigenetic changes in colorectal cancer prevention
Cancer Cell International (2025)
-
Roles of NOLC1 in cancers and viral infection
Journal of Cancer Research and Clinical Oncology (2023)
