1
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Wang YR, Wang PJ, Tao LY, Hu LL, Liu QQ, Sun SC, Wei JX, Wang Y. Loss of KIFC1 activity induces spindle instability and actin defects during porcine oocyte maturation. Theriogenology 2025; 235:254-261. [PMID: 39919850 DOI: 10.1016/j.theriogenology.2025.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 02/09/2025]
Abstract
KIFC1 is a motor protein of the Kinesin family and it is involved in spindle apparatus assembly, chromosome arrangement, and microfilament-mediated biological processes in mitosis. However, the specific function of KIFC1 in pig oocytes remains unclear. Here, in order to explore the function of KIFC1 in porcine oocytes, the AZ82 inhibitor was used to inhibit the activity of KIFC1. Our results showed when KIFC1 was inhibited, the polar body extrusion rate was obviously decreased, indicating that KIFC1 plays a crucial role in porcine oocytes. We next measured the spindle structure and chromosome arrangement via immunofluorescent staining and found both the rates of abnormal spindle and chromosome disorder increased significantly. By further analyzing the causes of the abnormal spindle, we found the acetylation of tubulin was disrupted. In addition, we also found the spindle position was impaired after KIFC1 inhibition, declaring the spindle migration was affected. Further analysis found cortex actin decreased and cytoplasmic actin increased after KIFC1 inhibition. In summary, we found that KIFC1 played a critical role in porcine oocytes maturation by controlling spindle apparatus via mediating the acetylation of microtubule and regulating the spindle migration via affecting actin dynamics.
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Affiliation(s)
- Yu-Ran Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Peng-Jie Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Le-Yan Tao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Lin-Lin Hu
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Reproductive Medicine of Guangxi Medical and Health Key Discipline Construction Project, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Qiang-Qiang Liu
- College of Foreign Studies, Nanjing Agricultural University, Nanjing, 210095, China
| | - Shao-Chen Sun
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China; Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Reproductive Medicine of Guangxi Medical and Health Key Discipline Construction Project, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Jing-Xi Wei
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Reproductive Medicine of Guangxi Medical and Health Key Discipline Construction Project, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
| | - Yue Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
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2
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Ems M, Brichkina A, Lauth M. A safe haven for cancer cells: tumor plus stroma control by DYRK1B. Oncogene 2025; 44:341-347. [PMID: 39863750 PMCID: PMC11790486 DOI: 10.1038/s41388-025-03275-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/18/2024] [Accepted: 01/14/2025] [Indexed: 01/27/2025]
Abstract
The development of resistance remains one of the biggest challenges in clinical cancer patient care and it comprises all treatment modalities from chemotherapy to targeted or immune therapy. In solid malignancies, drug resistance is the result of adaptive processes occurring in cancer cells or the surrounding tumor microenvironment (TME). Future therapy attempts will therefore benefit from targeting both, tumor and stroma compartments and drug targets which affect both sides will be highly appreciated. In this review, we describe a seemingly paradoxical oncogenic mediator with this potential: The dual-specificity tyrosine-phosphorylation regulated kinase 1B (DYRK1B). DYRK1B promotes proliferative quiescence and yet is overexpressed or amplified in many hyperproliferative malignancies including ovarian cancer and pancreatic cancer. In particular the latter disease is a paradigmatic example for a therapy-recalcitrant and highly stroma-rich cancer entity. Here, recent evidence suggests that DYRK1B exerts its oncogenic features by installing a protective niche for cancer cells by directly affecting cancer cells but also the TME. Specifically, DYRK1B not only fosters cell-intrinsic processes like cell survival, chemoresistance, and disease recurrence, but it also upregulates TME and cancer cell-protective innate immune checkpoints and down-modulates anti-tumoral macrophage functionality. In this article, we outline the well-established cell-autonomous roles of DYRK1B and extend its importance to the TME and the control of the tumor immune stroma. In summary, DYRK1B appears as a single novel key player creating a safe haven for cancer cells by acting cell-intrinsically and-extrinsically, leading to the promotion of cancer cell survival, chemoresistance, and relapse. Thus, DYRK1B appears as an attractive drug target for future therapeutic approaches.
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Affiliation(s)
- Miriam Ems
- Department of Gastroenterology, Endocrinology and Metabolism, Center for Tumor and Immune Biology, Philipps University Marburg, Marburg, Germany
| | - Anna Brichkina
- Institute of Systems Immunology, Philipps University Marburg, Marburg, Germany
| | - Matthias Lauth
- Department of Gastroenterology, Endocrinology and Metabolism, Center for Tumor and Immune Biology, Philipps University Marburg, Marburg, Germany.
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3
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Kokkorakis N, Zouridakis M, Gaitanou M. Mirk/Dyrk1B Kinase Inhibitors in Targeted Cancer Therapy. Pharmaceutics 2024; 16:528. [PMID: 38675189 PMCID: PMC11053710 DOI: 10.3390/pharmaceutics16040528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising pharmacological target in cancer since it is overexpressed in many tumors, and its overexpression is correlated with patients' poor prognosis. Mirk/Dyrk1B acts as a negative cell cycle regulator, maintaining the survival of quiescent cancer cells and conferring their resistance to chemotherapies. Many studies have demonstrated the valuable therapeutic effect of Mirk/Dyrk1B inhibitors in cancer cell lines, mouse xenografts, and patient-derived 3D-organoids, providing a perspective for entering clinical trials. Since the majority of Mirk/Dyrk1B inhibitors target the highly conserved ATP-binding site, they exhibit off-target effects with other kinases, especially with the highly similar Dyrk1A. In this review, apart from summarizing the data establishing Dyrk1B as a therapeutic target in cancer, we highlight the most potent Mirk/Dyrk1B inhibitors recently reported. We also discuss the limitations and perspectives for the structure-based design of Mirk/Dyrk1B potent and highly selective inhibitors based on the accumulated structural data of Dyrk1A and the recent crystal structure of Dyrk1B with AZ191 inhibitor.
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Affiliation(s)
- Nikolaos Kokkorakis
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, 15784 Athens, Greece
| | - Marios Zouridakis
- Structural Neurobiology Research Group, Laboratory of Molecular Neurobiology and Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Maria Gaitanou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, 11521 Athens, Greece;
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4
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Liu L, Liu X, Chen Y, Kong M, Zhang J, Jiang M, Zhou H, Yang J, Chen X, Zhang Z, Wu C, Jiang X, Zhang J. Paxillin/HDAC6 regulates microtubule acetylation to promote directional migration of keratinocytes driven by electric fields. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119628. [PMID: 37949303 DOI: 10.1016/j.bbamcr.2023.119628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 10/18/2023] [Accepted: 11/03/2023] [Indexed: 11/12/2023]
Abstract
Endogenous electric fields (EFs) have been demonstrated to facilitate wound healing by directing the migration of epidermal cells. Despite the identification of numerous molecules and signaling pathways that are crucial for the directional migration of keratinocytes under EFs, the underlying molecular mechanisms remain undefined. Previous studies have indicated that microtubule (MT) acetylation is linked to cell migration, while Paxillin exerts a significant influence on cell motility. Therefore, we postulated that Paxillin could enhance EF-induced directional migration of keratinocytes by modulating MT acetylation. In the present study, we observed that EFs (200 mV/mm) induced migration of human immortalized epidermal cells (HaCaT) towards the anode, while upregulating Paxillin, downregulating HDAC6, and increasing the level of microtubule acetylation. Our findings suggested that Paxillin plays a pivotal role in inhibiting HDAC6-mediated microtubule acetylation during directional migration under EF regulation. Conversely, downregulation of Paxillin decreased microtubule acetylation and electrotaxis of epidermal cells by promoting HDAC6 expression, and this effect could be reversed by the addition of tubacin, an HDAC6-specific inhibitor. Furthermore, we observed that EFs also mediated the polarization of Paxillin and acetylated α-tubulin, which is critical for directional migration. In conclusion, our study revealed that MT acetylation in EF-guided keratinocyte migration is regulated by the Paxillin/HDAC6 signaling pathway, providing a novel theoretical foundation for the molecular mechanism of EF-guided directional migration of keratinocytes.
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Affiliation(s)
- Luojia Liu
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Xiaoqiang Liu
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Ying Chen
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Meng Kong
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Jinghong Zhang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Min Jiang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Hongling Zhou
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Jinrui Yang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Xu Chen
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Ze Zhang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Chao Wu
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China
| | - Xupin Jiang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China.
| | - Jiaping Zhang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 400038 Chongqing, China.
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5
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Kwon Y, Choi Y, Kim M, Jo H, Jeong MS, Jung HS, Jeoung D. HDAC6-MYCN-CXCL3 axis mediates allergic inflammation and is necessary for allergic inflammation-promoted cellular interactions. Mol Immunol 2024; 166:1-15. [PMID: 38176167 DOI: 10.1016/j.molimm.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/27/2023] [Accepted: 12/18/2023] [Indexed: 01/06/2024]
Abstract
Histone deacetylase 6 (HDAC6) has been shown to play an important role in allergic inflammation. This study hypothesized that novel downstream targets of HDAC6 would mediate allergic inflammation. Experiments employing HDAC6 knock out C57BL/6 mice showed that HDAC6 mediated passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA). Antigen stimulation increased expression of N-myc (MYCN) and CXCL3 in an HDAC6-dependent manner in the bone marrow-derived mast cells. MYCN and CXCL3 were necessary for both PCA and PSA. The role of early growth response 3 (EGR3) in the regulation of HDAC6 expression has been reported. ChIP assays showed EGR3 as a direct regulator of MYCN. miR-34a-5p was predicted to be a negative regulator of MYCN. Luciferase activity assays showed miR-34a-5p as a direct regulator of MYCN. miR-34a-5p mimic negatively regulated PCA and PSA. MYCN decreased miR-34a-5p expression in antigen-stimulated rat basophilic leukemia cells (RBL2H3). MYCN was shown to bind to the promoter sequence of CXCL3. In an IgE-independent manner, recombinant CXCL3 protein increased expression of HDAC6, MYCN, and β-hexosaminidase activity in RBL2H3 cells. Mouse recombinant CXCL3 protein enhanced the angiogenic potential of the culture medium of RBL2H3. CXCL3 was necessary for the enhanced angiogenic potential of the culture medium of antigen-stimulated RBL2H3. The culture medium of RBL2H3 was able to induce M2 macrophage polarization in a CXCL3-dependent manner. Recombinant CXCL3 protein also increased the expression of markers of M2 macrophage. Thus, the identification of the novel role of HDAC6-MYCN-CXCL3 axis can help better understand the pathogenesis of anaphylaxis.
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Affiliation(s)
- Yoojung Kwon
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea
| | - Yunji Choi
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea
| | - Misun Kim
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, South Korea
| | - Hyein Jo
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea
| | - Myeong Seon Jeong
- Chuncheon Center, Korea Basic Science Institute, Chuncheon 24341, South Korea
| | - Hyun Suk Jung
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea
| | - Dooil Jeoung
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea.
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6
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Kokkorakis N, Douka K, Nalmpanti A, Politis PK, Zagoraiou L, Matsas R, Gaitanou M. Mirk/Dyrk1B controls ventral spinal cord development via Shh pathway. Cell Mol Life Sci 2024; 81:70. [PMID: 38294527 PMCID: PMC10830675 DOI: 10.1007/s00018-023-05097-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 12/14/2023] [Accepted: 12/17/2023] [Indexed: 02/01/2024]
Abstract
Cross-talk between Mirk/Dyrk1B kinase and Sonic hedgehog (Shh)/Gli pathway affects physiology and pathology. Here, we reveal a novel role for Dyrk1B in regulating ventral progenitor and neuron subtypes in the embryonic chick spinal cord (SC) via the Shh pathway. Using in ovo gain-and-loss-of-function approaches at E2, we report that Dyrk1B affects the proliferation and differentiation of neuronal progenitors at E4 and impacts on apoptosis specifically in the motor neuron (MN) domain. Especially, Dyrk1B overexpression decreases the numbers of ventral progenitors, MNs, and V2a interneurons, while the pharmacological inhibition of endogenous Dyrk1B kinase activity by AZ191 administration increases the numbers of ventral progenitors and MNs. Mechanistically, Dyrk1B overexpression suppresses Shh, Gli2 and Gli3 mRNA levels, while conversely, Shh, Gli2 and Gli3 transcription is increased in the presence of Dyrk1B inhibitor AZ191 or Smoothened agonist SAG. Most importantly, in phenotype rescue experiments, SAG restores the Dyrk1B-mediated dysregulation of ventral progenitors. Further at E6, Dyrk1B affects selectively the medial lateral motor neuron column (LMCm), consistent with the expression of Shh in this region. Collectively, these observations reveal a novel regulatory function of Dyrk1B kinase in suppressing the Shh/Gli pathway and thus affecting ventral subtypes in the developing spinal cord. These data render Dyrk1B a possible therapeutic target for motor neuron diseases.
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Affiliation(s)
- N Kokkorakis
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
- Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - K Douka
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
| | - A Nalmpanti
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
- Athens International Master's Programme in Neurosciences, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - P K Politis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - L Zagoraiou
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - R Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
| | - M Gaitanou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece.
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7
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Naren P, Samim KS, Tryphena KP, Vora LK, Srivastava S, Singh SB, Khatri DK. Microtubule acetylation dyshomeostasis in Parkinson's disease. Transl Neurodegener 2023; 12:20. [PMID: 37150812 PMCID: PMC10165769 DOI: 10.1186/s40035-023-00354-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/06/2023] [Indexed: 05/09/2023] Open
Abstract
The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system. This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back and forth from the soma to the synapse. Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde (from the soma to the synapse) and retrograde (from the synapse to the soma) commute of the cargos, respectively. Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications (PTMs) of α- and β-tubulin heterodimers, core components constructing the MTs. Occurring within the lumen of MTs, K40 acetylation of α-tubulin via α-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible, which in turn promotes their lifespan. The movement of various motor proteins, including kinesin-1 (responsible for axonal mitochondrial commute), is enhanced by this PTM, and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions, including Alzheimer's disease and Parkinson's disease (PD). PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels. Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question, our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD. The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored. Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it.
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Affiliation(s)
- Padmashri Naren
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Khan Sabiya Samim
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Kamatham Pushpa Tryphena
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Lalitkumar K Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
| | - Shashi Bala Singh
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Dharmendra Kumar Khatri
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
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8
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Hupfer A, Brichkina A, Adhikary T, Lauth M. The mammalian Hedgehog pathway is modulated by ANP32 proteins. Biochem Biophys Res Commun 2021; 553:78-84. [PMID: 33761414 DOI: 10.1016/j.bbrc.2021.03.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 03/05/2021] [Indexed: 12/29/2022]
Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. Transcriptional profiling has so far delineated four major MB subgroups of which one is driven by uncontrolled Hedgehog (Hh) signaling (SHH-MB). This pathway is amenable to drug targeting, yet clinically approved compounds exclusively target the transmembrane component Smoothened (SMO). Unfortunately, drug resistance against SMO inhibitors is encountered frequently, making the identification of novel Hh pathway components mandatory, which could serve as novel drug targets in the future. Here, we have used MB as a tool to delineate novel modulators of Hh signaling and have identified the Acidic Nuclear Phosphoprotein 32 (ANP32) family of proteins as novel regulators. The expression of all three family members (ANP32A, ANP32B, ANP32E) is increased in Hh-induced MB and their expression level is negatively associated with overall survival in SHH-MB patients. Mechanistically, we could find that ANP32 proteins function as positive modulators of mammalian Hh signaling upstream of GLI transcription factors. These findings add hitherto unknown regulators to the mammalian Hh signaling cascade and might spur future translational efforts to combat Hh-driven malignancies.
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Affiliation(s)
- Anna Hupfer
- Philipps University Marburg, Center for Tumor- and Immune Biology (ZTI), Clinics of Gastroenterology, Endocrinology, Metabolism and Infectiology, Germany
| | - Anna Brichkina
- Philipps University Marburg, Center for Tumor- and Immune Biology (ZTI), Clinics of Gastroenterology, Endocrinology, Metabolism and Infectiology, Germany
| | - Till Adhikary
- Philipps University Marburg, Center for Tumor Biology and Immunology (ZTI), Institute of Medical Bioinformatics and Biostatistics, Institute of Molecular Biology and Tumor Research, Germany
| | - Matthias Lauth
- Philipps University Marburg, Center for Tumor- and Immune Biology (ZTI), Clinics of Gastroenterology, Endocrinology, Metabolism and Infectiology, Germany.
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9
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Li L, Wei JR, Song Y, Fang S, Du Y, Li Z, Zeng TT, Zhu YH, Li Y, Guan XY. TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression. Cell Death Dis 2021; 12:125. [PMID: 33500384 PMCID: PMC7838256 DOI: 10.1038/s41419-021-03422-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/17/2020] [Accepted: 12/21/2020] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the common malignancy and lacks effective therapeutic targets. Here, we demonstrated that ectopic expression of trophinin-associated protein (TROAP) dramatically drove HCC cell growth assessed by foci formation in monolayer culture, colony formation in soft agar and orthotopic liver transplantation in nude mice. Inversely, silencing TROAP expression with short-hairpin RNA attenuated the malignant proliferation of HCC cells in vitro and in vivo. Next, mechanistic investigation revealed that TROAP directly bound to dual specificity tyrosine phosphorylation regulated kinase 1A/B (DYRK1A/B), resulting in the cytoplasmic retention of proteins DYRK1A/B and promoting cell cycle process via activation of Akt/GSK-3β signaling. Combination of cisplatin with an inhibitor of DYRK1 AZ191 effectively inhibited tumor growth in mouse model for HCC cells with high level of TROAP. Clinically, TROAP was significantly upregulated by miR-142-5p in HCC tissues, which predicted the poor survival of patients with HCC. Therefore, TROAP/DYRK1/Akt axis may be a promising therapeutic target and prognostic indicator for patients with HCC.
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Affiliation(s)
- Lei Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
- Department of Clinical Oncology, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
- Department of Clinical Oncology Center, The University of Hongkong-Shenzhen Hospital, 518053, Shenzhen, China.
| | - Jia-Ru Wei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 510060, Guangzhou, China
| | - Ye Song
- Affiliated Cancer Hospital & Institutes of Guangzhou Medical University, Guangzhou Key Medical Discipline Construction Project, 510095, Guangzhou, China
| | - Shuo Fang
- The Seventh Affiliated Hospital, Sun Yat-sen University, 518100, Shenzhen, China
| | - Yanyu Du
- The Seventh Affiliated Hospital, Sun Yat-sen University, 518100, Shenzhen, China
| | - Zhuo Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Ting-Ting Zeng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Ying-Hui Zhu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Yan Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
- Department of Clinical Oncology, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
- Department of Clinical Oncology Center, The University of Hongkong-Shenzhen Hospital, 518053, Shenzhen, China.
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10
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Kokkorakis N, Gaitanou M. Minibrain-related kinase/dual-specificity tyrosine-regulated kinase 1B implication in stem/cancer stem cells biology. World J Stem Cells 2020; 12:1553-1575. [PMID: 33505600 PMCID: PMC7789127 DOI: 10.4252/wjsc.v12.i12.1553] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/29/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), also known as minibrain-related kinase (MIRK) is one of the best functionally studied members of the DYRK kinase family. DYRKs comprise a family of protein kinases that are emerging modulators of signal transduction pathways, cell proliferation and differentiation, survival, and cell motility. DYRKs were found to participate in several signaling pathways critical for development and cell homeostasis. In this review, we focus on the DYRK1B protein kinase from a functional point of view concerning the signaling pathways through which DYRK1B exerts its cell type-dependent function in a positive or negative manner, in development and human diseases. In particular, we focus on the physiological role of DYRK1B in behavior of stem cells in myogenesis, adipogenesis, spermatogenesis and neurogenesis, as well as in its pathological implication in cancer and metabolic syndrome. Thus, understanding of the molecular mechanisms that regulate signaling pathways is of high importance. Recent studies have identified a close regulatory connection between DYRK1B and the hedgehog (HH) signaling pathway. Here, we aim to bring together what is known about the functional integration and cross-talk between DYRK1B and several signaling pathways, such as HH, RAS and PI3K/mTOR/AKT, as well as how this might affect cellular and molecular processes in development, physiology, and pathology. Thus, this review summarizes the major known functions of DYRK1B kinase, as well as the mechanisms by which DYRK1B exerts its functions in development and human diseases focusing on the homeostasis of stem and cancer stem cells.
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Affiliation(s)
- Nikolaos Kokkorakis
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens 11521, Greece
| | - Maria Gaitanou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens 11521, Greece.
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Montagnani V, Stecca B. Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy. Cancers (Basel) 2019; 11:cancers11040449. [PMID: 30934935 PMCID: PMC6520855 DOI: 10.3390/cancers11040449] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/20/2019] [Accepted: 03/26/2019] [Indexed: 02/08/2023] Open
Abstract
Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant reactivation of HH signaling has been associated to several types of cancer, including those in the skin, brain, prostate, breast and hematological malignancies. Activation of the canonical HH signaling is triggered by binding of HH ligand to the twelve-transmembrane protein PATCHED. The binding releases the inhibition of the seven-transmembrane protein SMOOTHENED (SMO), leading to its phosphorylation and activation. Hence, SMO activates the transcriptional effectors of the HH signaling, that belong to the GLI family of transcription factors, acting through a not completely elucidated intracellular signaling cascade. Work from the last few years has shown that protein kinases phosphorylate several core components of the HH signaling, including SMO and the three GLI proteins, acting as powerful regulatory mechanisms to fine tune HH signaling activities. In this review, we will focus on the mechanistic influence of protein kinases on HH signaling transduction. We will also discuss the functional consequences of this regulation and the possible implications for cancer therapy.
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Affiliation(s)
- Valentina Montagnani
- Core Research Laboratory⁻Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 50139 Florence, Italy.
| | - Barbara Stecca
- Core Research Laboratory⁻Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 50139 Florence, Italy.
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