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

Author:

Huang Rongsheng1,Yamamoto Takahiro2,Nakata Eiji3,Ozaki Toshifumi3,Kurozumi Kazuhiko4,Wei Fanyan5,Tomizawa Kazuhito2,Fujimura Atsushi16ORCID

Affiliation:

1. Department of Cellular Physiology Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Okayama 700‐8558 Japan

2. Department of Molecular Physiology Kumamoto University Faculty of Life Sciences Kumamoto Kumamoto 860‐0811 Japan

3. Department of Orthopedic Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Okayama 700‐8558 Japan

4. Department of Neurosurgery Hamamatsu University School of Medicine Hamamatsu Shizuoka 431‐3192 Japan

5. Department of Modomics Biology and Medicine Institute of Development, Aging and Cancer Tohoku University Sendai Miyagi 980‐8575 Japan

6. Neutron Therapy Research Center Okayama University Okayama Okayama 700‐8558 Japan

Abstract

AbstractCancer 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.

Funder

Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

Publisher

Wiley

Subject

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

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