CDKAL1 Drives the Maintenance of Cancer Stem-Like Cells by Assembling the eIF4F Translation Initiation Complex

Rongsheng Huang; Takahiro Yamamoto; Eiji Nakata; Toshifumi Ozaki; Kazuhiko Kurozumi; Fanyan Wei; Kazuhito Tomizawa; Atsushi Fujimura

doi:10.1002/advs.202206542

CDKAL1 Drives the Maintenance of Cancer Stem-Like Cells by Assembling the eIF4F Translation Initiation Complex

Rongsheng Huang, Takahiro Yamamoto, Eiji Nakata, Toshifumi Ozaki, Kazuhiko Kurozumi, Fanyan Wei, Kazuhito Tomizawa, Atsushi Fujimura

Research output: Contribution to journal › Article › peer-review

Abstract

Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5’ untranslated region (5’UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH₂-terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.

Original language	English
Journal	Advanced Science
DOIs	https://doi.org/10.1002/advs.202206542
Publication status	Accepted/In press - 2023

Keywords

cancer stem-like cells
CDKAL1
CG-rich 5’UTR
eIF4F complex
SALL2

ASJC Scopus subject areas

Medicine (miscellaneous)
Chemical Engineering(all)
Materials Science(all)
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Engineering(all)
Physics and Astronomy(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/advs.202206542

Cite this

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title = "CDKAL1 Drives the Maintenance of Cancer Stem-Like Cells by Assembling the eIF4F Translation Initiation Complex",

abstract = "Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5{\textquoteright} untranslated region (5{\textquoteright}UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH2-terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.",

keywords = "cancer stem-like cells, CDKAL1, CG-rich 5{\textquoteright}UTR, eIF4F complex, SALL2",

author = "Rongsheng Huang and Takahiro Yamamoto and Eiji Nakata and Toshifumi Ozaki and Kazuhiko Kurozumi and Fanyan Wei and Kazuhito Tomizawa and Atsushi Fujimura",

note = "Funding Information: The authors thank H. Wakimoto for gifts of MGG cells, D. Friedmann‐Morvinski for pTomo‐HRas/shp53 plasmid and colleagues sharing their plasmids through Addgene (B. Weinberg, I. Verma, and D. Trono). The authors are grateful to the Central Research Laboratory, Okayama University Medical School for support in FACS, confocal microscopy, and electron microscopy. The authors thank S. Yoshikawa for technical support in FACS and all members in our laboratory for valuable comments. The authors also thank Enago for English language processing and editing. This work was supported by the Grant‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan (grant number JP20K07618) and the Japan Agency for Medical Research and Developmen (AMED) (grant numbers JP18cm0106143 and JP20cm0106179) and the Naito Foundation. Publisher Copyright: {\textcopyright} 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.",

year = "2023",

doi = "10.1002/advs.202206542",

language = "English",

journal = "Advanced Science",

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AU - Huang, Rongsheng

AU - Yamamoto, Takahiro

AU - Nakata, Eiji

AU - Ozaki, Toshifumi

AU - Kurozumi, Kazuhiko

AU - Wei, Fanyan

AU - Tomizawa, Kazuhito

AU - Fujimura, Atsushi

N1 - Funding Information: The authors thank H. Wakimoto for gifts of MGG cells, D. Friedmann‐Morvinski for pTomo‐HRas/shp53 plasmid and colleagues sharing their plasmids through Addgene (B. Weinberg, I. Verma, and D. Trono). The authors are grateful to the Central Research Laboratory, Okayama University Medical School for support in FACS, confocal microscopy, and electron microscopy. The authors thank S. Yoshikawa for technical support in FACS and all members in our laboratory for valuable comments. The authors also thank Enago for English language processing and editing. This work was supported by the Grant‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan (grant number JP20K07618) and the Japan Agency for Medical Research and Developmen (AMED) (grant numbers JP18cm0106143 and JP20cm0106179) and the Naito Foundation. Publisher Copyright: © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

PY - 2023

Y1 - 2023

N2 - Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5’ untranslated region (5’UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH2-terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.

AB - Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5’ untranslated region (5’UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH2-terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.

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KW - eIF4F complex

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DO - 10.1002/advs.202206542

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JO - Advanced Science

JF - Advanced Science

ER -

CDKAL1 Drives the Maintenance of Cancer Stem-Like Cells by Assembling the eIF4F Translation Initiation Complex

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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