m 6 A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5

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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, m ⁶A methylation participated in the upregulation of CBX8 by maintaining CBX8 mRNA stability.

Conclusions

Upon m ⁶A 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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METTL3 facilitates tumor progression via an m 6 A-IGF2BP2-dependent mechanism in colorectal carcinoma

Ting Li, Pei-Shan Hu, Zhixiang Zuo … (2019)

Background Colorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored. Methods Western blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3. Results Using TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were subsequently recognized by the specific m6A “reader”, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including “writer”, “reader”, and “target”, exhibited a better prognostic value for CRC patients than any of these components individually. Conclusions Overall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an m6A-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC. Electronic supplementary material The online version of this article (10.1186/s12943-019-1038-7) contains supplementary material, which is available to authorized users.

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Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells.

Hans Clevers, Hans Rodermond, Wim de Visser … (2012)

In colorectal cancer (CRC), a subpopulation of tumor cells, called cancer stem cell (CSC) fraction, is suggested to be responsible for tumor initiation, growth, and metastasis. The search for a reliable marker to identify these CSCs is ongoing as current markers, like CD44 and CD133, are more broadly expressed and therefore are not highly selective and currently also lack function in CSC biology. Here, we analyzed whether the Wnt target Lgr5, which has earlier been identified as a marker for murine intestinal stem cells, could potentially serve as a functional marker for CSCs. Fluorescence-activated cell sorting-based detection of Lgr5, using three newly developed antibodies, on primary colorectal tumor cells revealed a clear subpopulation of Epcam+ Lgr5+ cells. Similarly, primary CRC-derived spheroid cultures, known to be enriched for CSCs, contain high levels of Lgr5+ cells, which decrease upon in vitro differentiation of these CSCs. Selection of the Lgr5(high) CRC cells identified the clonogenic fraction in vitro as well as the tumorigenic population in vivo. Finally, we confirm that Lgr5 expression is dependent on the Wnt pathway and show that Lgr5 overexpression induces clonogenic growth. We thus provide evidence that Lgr5 is, next to a functional intestinal stem cell marker, a selective marker for human colorectal CSCs. Copyright © 2012 AlphaMed Press.

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Cancer stem cells: A contentious hypothesis now moving forward.

Michael O'Connor, Dongxi Xiang, Sarah Shigdar … (2014)

Cancer stem cells are a progressive concept to account for the cell biological nature of cancer. Despite the controversies regarding the cancer stem cell model, it has the potential to provide a foundation for new innovative treatment targeting the roots of cancer. The last two years have witnessed exceptional progress in cancer stem cell research, in particular on solid tumours, which holds promise for improved treatment outcomes. Here, we review recent advances in cancer stem cell research, discuss challenges in the field and explore future strategies and opportunities in cancer stem cell studies to overcome resistance to chemotherapy. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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Author and article information

Contributors

Fumio Shimamoto: fshimamo@shudo-u.ac.jp

Bo Tang: dr_sntangbo@163.com

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 18 December 2019

Publication date PMC-release: 18 December 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 185

Affiliations

[1 ]ISNI 0000 0001 0741 057X, GRID grid.443705.1, Department of Health Sciences, , Hiroshima Shudo University, ; 1-1-1, Ozuka-higashi, Asaminami-ku, Hiroshima, 731-3195 Japan

[2 ]GRID grid.413389.4, Department of General Surgery, , Affiliated hospital of Xuzhou Medical University, ; Xuzhou, 221000 China

[3 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Obstetrics, Gynecology and Reproductive Sciences, , Yale School of Medicine, ; New Haven, CT 06510 USA

[4 ]GRID grid.452435.1, Department of Oncology, , The First Affiliated Hospital of Dalian Medical University, ; Dalian, 116011 China

Article

Publisher ID: 1116

DOI: 10.1186/s12943-019-1116-x

PMC ID: 6918584

PubMed ID: 31849331

SO-VID: efbbe05d-b9f9-4a04-8202-b450457b0d2c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 September 2019

Date accepted : 3 December 2019

Funding

Funded by: National Natural Science Foundation of China (CN)

Award ID: 81702435

Award Recipient : Yi Zhang

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81871938

Award ID: 81560393

Award Recipient : Bo Tang

Funded by: FundRef http://dx.doi.org/10.13039/501100004608, Natural Science Foundation of Jiangsu Province;

Award ID: BK20170264

Award Recipient : Yi Zhang

Funded by: FundRef http://dx.doi.org/10.13039/501100002858, China Postdoctoral Science Foundation;

Award ID: 2018M630606

Award Recipient : Yi Zhang

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: colon cancer,cancer stemness,m6a,cbx8

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: colon cancer, cancer stemness, m6a, cbx8

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