Forced expression of DYRK2 exerts anti-tumor effects via apoptotic induction in liver cancer

Yokoyama-Mashima, Shiho; Yogosawa, Satomi; Kanegae, Yumi; Hirooka, Shinichi; Yoshida, Saishu; Horiuchi, Takashi; Ohashi, Toya; Yanaga, Katsuhiko; Saruta, Masayuki; Oikawa, Tsunekazu; Yoshida, Kiyotsugu

doi:10.1016/j.canlet.2019.02.046

Cited by 31 publications

(43 citation statements)

References 35 publications

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“…To validate this suppression of Hh signaling by Dyrk2- deletion, we performed a transient over-expression experiment using wild-type human DYRK2 or a DYRK2-K251R construct that expresses a kinase dead mutant ( Taira et al, 2012 ; Figure 3—figure supplement 1C–D ) in Dyrk2 -/- MEFs using adenovirus infection ( Yokoyama-Mashima et al, 2019 ). Over-expression of the wild-type DYRK2 construct restored significant induction of Gli1 and Ptch1 expression upon exposure to SAG ( Figure 3D , Figure 3—figure supplement 1D ).…”

Section: Resultsmentioning

confidence: 99%

The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

Yoshida

Aoki

Fujiwara

et al. 2020

eLife

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Mammalian Hedgehog (Hh) signaling plays key roles in embryogenesis and uniquely requires primary cilia. Functional analyses of several ciliogenesis-related genes led to the discovery of the developmental diseases known as ciliopathies. Hence, identification of mammalian factors that regulate ciliogenesis can provide insight into the molecular mechanisms of embryogenesis and ciliopathy. Here, we demonstrate that DYRK2 acts as a novel mammalian ciliogenesis-related protein kinase. Loss of Dyrk2 in mice causes suppression of Hh signaling and results in skeletal abnormalities during in vivo embryogenesis. Deletion of Dyrk2 induces abnormal ciliary morphology and trafficking of Hh pathway components. Mechanistically, transcriptome analyses demonstrate down-regulation of Aurka and other disassembly genes following Dyrk2 deletion. Taken together, the present study demonstrates for the first time that DYRK2 controls ciliogenesis and is necessary for Hh signaling during mammalian development.

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Section: Resultsmentioning

confidence: 99%

The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

Yoshida

Aoki

Fujiwara

et al. 2020

eLife

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“…More recently, a novel approach using the adenovirus‐mediated over‐expression of DYRK2 has been reported . Notably, over‐expression of DYRK2 inhibits tumor growth of liver cancer cells via both an induction of apoptosis and inhibition of cell proliferation in xenograft model (Fig.…”

Section: Functions Of Dyrk2 In Cancermentioning

confidence: 99%

Multiple functions of DYRK2 in cancer and tissue development

Yoshida

2019

FEBS Letters

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Dual‐specificity tyrosine‐regulated kinases (DYRKs) are evolutionarily conserved from yeast to mammals. Accumulating studies have revealed that DYRKs have important roles in regulation of the cell cycle and survival. DYRK2, a member of the class II DYRK family protein, is a key regulator of p53, and phosphorylates it at Ser46 to induce apoptosis in response to DNA damage. Moreover, recent studies have uncovered that DYRK2 regulates G1/S transition, epithelial‐mesenchymal‐transition, and stemness in human cancer cells. DYRK2 also appears to have roles in tissue development in lower eukaryotes. Thus, the elucidation of mechanisms for DYRK2 during mammalian tissue development will promote the understanding of cell differentiation, tissue homeostasis, and congenital diseases as well as cancer. In this review, we discuss the roles of DYRK2 in tumor cells. Moreover, we focus on DYRK2‐dependent developmental mechanisms in several species including fly (Drosophila), worm (Caenorhabditis elegans), zebrafish (Danio rerio), and mammals.

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“…DYRK2 can also regulate cancer invasion and metastasis by degrading Snail; therefore, shRNA silencing of DYRK2 promoted tumor invasion and metastasis in immunodeficient mice subcutaneously implanted with MCF-7 cells 82 . Further supporting a tumor-suppressive function for DYRK2 and the potential of DYRK2 stabilization as an anticancer therapy, ectopic expression of DYRK2 inhibits cell proliferation, induces cell death, and prevents tumor growth in liver cancer 83 . As part of a regulatory feedback loop, DYRK2 enhances proteasomal degradation via phosphorylation of the 19S…”

Section: Dyrk2mentioning

confidence: 84%

“…Vitamin K3 was important for validating the role of KLF4-DYRK2 in the self-renewal of CML LSCs but might not be the appropriate drug for clinical translation because of toxicities to red blood cells, highlighting the need for novel small molecules with the same properties but enhanced safety in patients. Pharmacological stabilization of the DYRK2 protein is expected to be beneficial for CML patients, as it abrogates the self-renewal capacity of LSCs by depleting c-MYC and induces their apoptosis by activating p53 80,83,87 . The limited data on the physiological functions of DYRK2 in tissue homeostasis suggests that transient upregulation of DYRK2 may not be toxic to normal tissues, although further safety studies of identified DYRK2 stabilizers need to be conducted in preclinical studies.…”

Section: Future Directionsmentioning

confidence: 99%

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

Park

Lacorazza

2020

Exp Mol Med

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Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the development of more potent tyrosine kinase inhibitors to induce a durable deep molecular response, more than half of patients relapse upon treatment discontinuation. This clinical finding supports the paradigm that leukemia stem cells feed the neoplasm, resist tyrosine kinase inhibition, and reactivate upon drug withdrawal depending on the fitness of the patient’s immune surveillance. This concept lends support to the idea that treatment-free remission is not achieved solely with tyrosine kinase inhibitors and that new molecular targets independent of BCR-ABL1 signaling are needed in order to develop adjuvant therapy to more efficiently eradicate the leukemia stem cell population responsible for chemoresistance and relapse. Future efforts must focus on the identification of new targets to support the discovery of potent and safe small molecules able to specifically eradicate the leukemic stem cell population. In this review, we briefly discuss molecular maintenance in leukemia stem cells in chronic myeloid leukemia and provide a more in-depth discussion of the dual-specificity kinase DYRK2, which has been identified as a novel actionable checkpoint in a critical leukemic network. DYRK2 controls the activation of p53 and proteasomal degradation of c-MYC, leading to impaired survival and self-renewal of leukemia stem cells; thus, pharmacological activation of DYRK2 as an adjuvant to standard therapy has the potential to induce treatment-free remission.

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Forced expression of DYRK2 exerts anti-tumor effects via apoptotic induction in liver cancer

Cited by 31 publications

References 35 publications

The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

Multiple functions of DYRK2 in cancer and tissue development

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

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