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Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | Research

RETRACTED ARTICLE: m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5

Authors: Yi Zhang, Min Kang, Bin Zhang, Fanchao Meng, Jun Song, Hiroshi Kaneko, Fumio Shimamoto, Bo Tang

Published in: Molecular Cancer | Issue 1/2019

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Abstract

Background

Colon cancer (CC) cells can exhibit stemness and expansion capabilities, which contribute to resistance to conventional chemotherapies. Aberrant expression of CBX8 has been identified in many types of cancer, but the cause of this aberrant CBX8 expression and whether CBX8 is associated with stemness properties in CC remain unknown.

Methods

qRT-PCR and IHC were applied to examine CBX8 levels in normal and chemoresistant CC tissues. Cancer cell stemness and chemosensitivity were evaluated by spheroid formation, colony formation, Western blot and flow cytometry assays. RNA-seq combined with ChIP-seq was used to identify target genes, and ChIP, IP and dual luciferase reporter assays were applied to explore the underlying mechanisms.

Results

CBX8 was significantly overexpressed in chemoresistant CC tissues. In addition, CBX8 could promote stemness and suppress chemosensitivity through LGR5. Mechanistic studies revealed that CBX8 activate the transcription of LGR5 in a noncanonical manner with assistance of Pol II. CBX8 recruited KMT2b to the LGR5 promoter, which maintained H3K4me3 status to promote LGR5 expression. Moreover, m6A methylation participated in the upregulation of CBX8 by maintaining CBX8 mRNA stability.

Conclusions

Upon m6A methylation-induced upregulation, CBX8 interacts with KMT2b and Pol II to promote LGR5 expression in a noncanonical manner, which contributes to increased cancer stemness and decreased chemosensitivity in CC. This study provides potential new therapeutic targets and valuable prognostic markers for CC.
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Literature
1.
2.
3.
Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717–28.CrossRefPubMed
4.
Zhang CZ, Chen SL, Wang CH, He YF, Yang X, Xie D, et al. CBX8 exhibits oncogenic activity via AKT/beta-catenin activation in hepatocellular carcinoma. Cancer Res. 2018;78:51–63.CrossRefPubMed
5.
Chung CY, Sun Z, Mullokandov G, Bosch A, Qadeer ZA, Cihan E, et al. Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis. Cell Rep. 2016;16:472–86.CrossRefPubMedPubMedCentral
6.
Yang S, Liu W, Li M, Wen J, Zhu M, Xu S. Insulin-like growth Factor-1 modulates Polycomb Cbx8 expression and inhibits Colon Cancer cell apoptosis. Cell Biochem Biophys. 2015;71:1503–7.CrossRefPubMed
7.
Tang J, Wang G, Zhang M, Li FY, Sang Y, Wang B, et al. Paradoxical role of CBX8 in proliferation and metastasis of colorectal cancer. Oncotarget. 2014;5:10778–90.CrossRefPubMedPubMedCentral
8.
Bardos JI, Saurin AJ, Tissot C, Duprez E, Freemont PS. HPC3 is a new human polycomb orthologue that interacts and associates with RING1 and Bmi1 and has transcriptional repression properties. J Biol Chem. 2000;275:28785–92.CrossRefPubMed
9.
Tan J, Jones M, Koseki H, Nakayama M, Muntean AG, Maillard I, et al. CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell. 2011;20:563–75.CrossRefPubMedPubMedCentral
10.
Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature. 2017;545:187–92.CrossRefPubMed
11.
Du L, Li YJ, Fakih M, Wiatrek RL, Duldulao M, Chen Z, et al. Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal. Nat Commun. 2016;7:12326.CrossRefPubMedPubMedCentral
12.
Zhu Y, Wang C, Becker SA, Hurst K, Nogueira LM, Findlay VJ, et al. miR-145 Antagonizes SNAI1-Mediated Stemness and Radiation Resistance in Colorectal Cancer. Mol Ther. 2018;26:744–54.CrossRefPubMedPubMedCentral
13.
Wang X, Li L, Wu Y, Zhang R, Zhang M, Liao D, et al. CBX4 suppresses metastasis via recruitment of HDAC3 to the Runx2 promoter in colorectal carcinoma. Cancer Res. 2016;76:7277–89.CrossRefPubMed
14.
Beguelin W, Teater M, Gearhart MD, Calvo Fernandez MT, Goldstein RL, Cardenas MG, et al. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and Lymphomagenesis. Cancer Cell. 2016;30:197–213.CrossRefPubMedPubMedCentral
15.
Tomizawa SI, Kobayashi Y, Shirakawa T, Watanabe K, Mizoguchi K, Hoshi I, et al. Kmt2b conveys monovalent and bivalent H3K4me3 in mouse spermatogonial stem cells at germline and embryonic promoters. Development. 2018;145:dev169102.CrossRefPubMed
16.
Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18:31–42.CrossRefPubMed
17.
18.
Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95.CrossRefPubMedPubMedCentral
19.
O'Connor ML, Xiang D, Shigdar S, Macdonald J, Li Y, Wang T, et al. Cancer stem cells: a contentious hypothesis now moving forward. Cancer Lett. 2014;344:180–7.CrossRefPubMed
20.
Klauke K, Radulovic V, Broekhuis M, Weersing E, Zwart E, Olthof S, et al. Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat Cell Biol. 2013;15:353–62.CrossRefPubMed
21.
22.
Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6:25–36.CrossRefPubMed
23.
Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–11.CrossRefPubMed
24.
Kemper K, Prasetyanti PR, De Lau W, Rodermond H, Clevers H, Medema JP. Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells. 2012;30:2378–86.CrossRefPubMed
25.
Hirsch D, Barker N, McNeil N, Hu Y, Camps J, McKinnon K, et al. LGR5 positivity defines stem-like cells in colorectal cancer. Carcinogenesis. 2014;35:849–58.CrossRefPubMed
26.
Liu YS, Hsu HC, Tseng KC, Chen HC, Chen SJ. Lgr5 promotes cancer stemness and confers chemoresistance through ABCB1 in colorectal cancer. Biomed Pharmacother. 2013;67:791–9.CrossRefPubMed
27.
Zhang S, Chatterjee T, Godoy C, Wu L, Liu QJ, Carmon KS. GPR56 drives colorectal tumor growth and promotes drug resistance through upregulation of MDR1 expression via a RhoA-mediated mechanism. Mol Cancer Res. 2019;17:2196–2207.CrossRefPubMed
28.
Di Croce L, Helin K. Transcriptional regulation by Polycomb group proteins. Nat Struct Mol Biol. 2013;20:1147–55.CrossRefPubMed
29.
Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, et al. Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus. EMBO J. 2007;26:1637–48.CrossRefPubMedPubMedCentral
30.
Guenther MG, Jenner RG, Chevalier B, Nakamura T, Croce CM, Canaani E, et al. Global and Hox-specific roles for the MLL1 methyltransferase. Proc Natl Acad Sci U S A. 2005;102:8603–8.CrossRefPubMedPubMedCentral
31.
Barbagiovanni G, Germain P-L, Zech M, Atashpaz S, Lo Riso P, D’Antonio-Chronowska A, et al. KMT2B is selectively required for neuronal Transdifferentiation, and its loss exposes dystonia candidate genes. Cell Rep. 2018;25:988–1001.CrossRefPubMedPubMedCentral
32.
Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, et al. METTL3 facilitates tumor progression via an m(6)A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 2019;18:112.CrossRefPubMedPubMedCentral
33.
Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, et al. Essential role of METTL3-mediated m(6) a modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2018;37:522–33.CrossRefPubMed
34.
Lan Q, Liu PY, Haase J, Bell JL, Huttelmaier S, Liu T. The critical role of RNA m(6) a methylation in Cancer. Cancer Res. 2019;79:1285–92.CrossRefPubMed
Metadata
Title
RETRACTED ARTICLE: m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5
Authors
Yi Zhang
Min Kang
Bin Zhang
Fanchao Meng
Jun Song
Hiroshi Kaneko
Fumio Shimamoto
Bo Tang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-019-1116-x

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