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

Huang, Rongsheng; Yamamoto, Takahiro; Nakata, Eiji; Ozaki, Toshifumi; Kurozumi, Kazuhiko; Wei, Fan‐Yan; Tomizawa, Kazuhito; Fujimura, Akiko

doi:10.1002/advs.202206542

Cited by 4 publications

(2 citation statements)

References 53 publications

(75 reference statements)

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“…Immuno uorescent analysis and confocal microscopy: Immuno uorescent analysis on the breast cancer tissue array was performed as previously described [15]. The breast cancer tissue array was purchased from TissueArray.com (catalog number: BRM961a).…”

Section: (4) Materials and Methodsmentioning

confidence: 99%

The Role of C1orf50 in Breast Cancer Progression and Prognosis

Otani,

Tanaka,

Maekawa

et al. 2024

Preprint

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Although the prognosis of breast cancer has significantly improved compared to other types of cancer, there are still some patients who expire due to recurrence or metastasis. Therefore, it is necessary to develop a method to identify patients with poor prognosis at the early stages of cancer. In the process of discovering new prognostic markers from genes of unknown function, we found that the expression of C1orf50 determines the prognosis of breast cancer patients, especially for those with Luminal A breast cancer. This study aims to elucidate the molecular role of C1orf50 in breast cancer progression. Bioinformatic analyses of the breast cancer dataset of TCGA, and in vitro analyses, reveal the molecular pathways influenced by C1orf50 expression. C1orf50 knockdown suppressed the cell cycle of breast cancer cells and weakened their ability to maintain the undifferentiated state and self-renewal capacity. Interestingly, upregulation of C1orf50 increased sensitivity to CDK4/6 inhibition. In addition, C1orf50 was found to be more abundant in breast cancer cells than in normal breast epithelium, suggesting C1orf50 involvement in breast cancer pathogenesis. Furthermore, the mRNA expression level of C1orf50 was positively correlated with the expression of PD-L1 and its related factors. These results suggest that C1orf50 promotes breast cancer progression through cell cycle upregulation, maintenance of cancer stemness and immune evasion mechanisms. Our study uncovers the biological functions of C1orf50 in Luminal breast cancer progression, a finding not previously reported in any type of cancer.

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Section: (4) Materials and Methodsmentioning

confidence: 99%

The Role of C1orf50 in Breast Cancer Progression and Prognosis

Otani,

Tanaka,

Maekawa

et al. 2024

Preprint

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“…Human promyelocytic leukemia cells HL-60 were cultured in RPMI-1640 medium (Fujifilm Wako Pure Chemical, Osaka, Japan) supplemented with 20% fetal bovine serum (Nichirei Biosciences, Tokyo, Japan) and antibiotics (Fujifilm Wako Pure Chemical). Lentivirus preparation and infection were performed as previously reported [ 22 ]. Briefly, 293FT cells were transfected with 10 µg of pLKO.1 puro lentiviral backbone plasmid (Addgene #8453), 7.5 µg of psPAX2 (Addgene #12260), and 2.5 µg of pMD2.G (Addgene #12259) using TransIT-LT1 transfection reagent (TaKaRa Bio) and Opti-MEM (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Connective tissue mast cells store and release noradrenaline

Otani,

Yoshikawa,

Nagao

et al. 2023

J Physiol Sci

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Mast cells are present in mucosal and connective tissues throughout the body. They synthesize and release a wide variety of bioactive molecules, such as histamine, proteases, and cytokines. In this study, we found that a population of connective tissue mast cells (CTMCs) stores and releases noradrenaline, originating from sympathetic nerves. Noradrenaline-storing cells, not neuronal fibers, were predominantly identified in the connective tissues of the skin, mammary gland, gastrointestinal tract, bronchus, thymus, and pancreas in wild-type mice but were absent in mast cell–deficient W-sash c-kit mutant KitW−sh/W−sh mice. In vitro studies using bone marrow–derived mast cells revealed that extracellular noradrenaline was taken up but not synthesized. Upon ionomycin stimulation, noradrenaline was released. Electron microscopy analyses further suggested that noradrenaline is stored in and released from the secretory granules of mast cells. Finally, we found that noradrenaline-storing CTMCs express organic cation transporter 3 (Oct3), which is also known as an extraneuronal monoamine transporter, SLC22A3. Our findings indicate that mast cells may play a role in regulating noradrenaline concentration by storing and releasing it in somatic tissues.

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

et al. 2023

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

Cited by 4 publications

References 53 publications

The Role of C1orf50 in Breast Cancer Progression and Prognosis

The Role of C1orf50 in Breast Cancer Progression and Prognosis

Connective tissue mast cells store and release noradrenaline

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

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