RBM15 facilitates laryngeal squamous cell carcinoma progression by regulating TMBIM6 stability through IGF2BP3 dependent

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Abstract

Background

Laryngeal cancer has the highest mortality rate among head and neck tumours. RNA N6-methyladenosine (m6A) is the most plentiful and variable in mammalian mRNA. Yet, the m6A regulatory mechanism underlying the carcinogenesis or progression of LSCC remains poorly understood.

Methods

The m6A RNA methylation quantification kit was used to detect tissue methylation levels. m6A microarray analysis, mRNA transcriptomic sequencing (mRNA-seq), and proteomics were used to determine RBM15, TMBIM6, and IGF2BP3. Immunohistochemical (IHC), quantitative real-time PCR (qRT-PCR) and Western blot were used to investigate RBM15, TMBIM6, and IGF2BP3 expression in tissue samples and cell lines. The biological effects of RBM15 were detected both in vitro and in vivo. The combination relationship between RBM15/IGF2BP3 and TMBIM6 was verified by RNA immunoprecipitation (RIP) assay, Methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNase Mazf, and luciferase report assay. RNase Mazf was used to determine the methylation site on TMBIM6 mRNA. Hoechst staining assay was used to confirm the apoptotic changes. The actinomycin D verified TMBIM6 stability.

Results

The global mRNA m6A methylation level significantly increased in LSCC patients. RBM15, as a “writer” of methyltransferase, was significantly increased in LSCC and was associated with unfavorable prognosis. The knockdown of RBM15 reduced the proliferation, invasion, migration, and apoptosis of LSCC both in vitro and in vivo. The results were reversed after overexpressing RBM15. Mechanically, TMBIM6 acted as a downstream target of RBM15-mediated m6A modification. Furthermore, RBM15-mediated m6A modification of TMBIM6 mRNA enhanced TMBIM6 stability through IGF2BP3-dependent.

Conclusion

Our results revealed the essential roles of RBM15 and IGF2BP3 in m6A methylation modification in LSCC, thus identifying a novel RNA regulatory mechanism.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13046-021-01871-4.

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Most cited references 39

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Cancer Statistics, 2017.

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2017)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017;67:7-30. © 2017 American Cancer Society.

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Recognition of RNA N 6 -methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

Huilin Huang, Hengyou Weng, Wenju Sun … (2018)

N 6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTHDF2, IGF2BPs promote the stability and storage of their target mRNAs (e.g., MYC) in an m6A-depedent manner under normal and stress conditions and thus affect gene expression output. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Our work therefore reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.

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m(6)A RNA methylation promotes XIST-mediated transcriptional repression.

Deepak Patil, Chun-Kan Chen, Brian F Pickering … (2016)

The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N(6)-methyladenosine (m(6)A) residues-a reversible base modification of unknown function in long non-coding RNAs. We show that m(6)A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m(6)A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m(6)A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m(6)A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m(6)A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m(6)A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m(6)A. These data reveal a pathway of m(6)A formation and recognition required for XIST-mediated transcriptional repression.

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Author and article information

Contributors

Peng Wang: wangpengpublic@163.com

Yanan Sun: h04015@hrbmu.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J Exp Clin Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 26 February 2021

Publication date PMC-release: 26 February 2021

Publication date Collection: 2021

Volume: 40

Electronic Location Identifier: 80

Affiliations

GRID grid.412463.6, ISNI 0000 0004 1762 6325, Department of Otorhinolaryngology, Head and Neck Surgery, , The Second Affiliated Hospital, Harbin Medical University, ; Harbin, 150086 China

Article

Publisher ID: 1871

DOI: 10.1186/s13046-021-01871-4

PMC ID: 7912894

PubMed ID: 33637103

SO-VID: 0958b251-c8a7-42ce-b491-5a603e396768

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

History

Date received : 23 November 2020

Date accepted : 8 February 2021

Funding

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

Award ID: 81772874

Award ID: 81272965

Award Recipient : Yanan Sun

Funded by: FundRef http://dx.doi.org/10.13039/501100010031, Postdoctoral Research Foundation of China;

Award ID: 2020M670926

Award Recipient : Peng Wang

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: laryngeal squamous cell cancer (lscc),n6-methyladenosine (m6a),rna binding motif protein 15 (rbm15),tmbim6,igf2bp3

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: laryngeal squamous cell cancer (lscc), n6-methyladenosine (m6a), rna binding motif protein 15 (rbm15), tmbim6, igf2bp3

RBM15 facilitates laryngeal squamous cell carcinoma progression by regulating TMBIM6 stability through IGF2BP3 dependent

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Abstract

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Supplementary Information

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Cancer Immunotherapy

Most cited references 39

Cancer Statistics, 2017.

Recognition of RNA N 6 -methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

m(6)A RNA methylation promotes XIST-mediated transcriptional repression.

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