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1.
Nature ; 626(7998): 411-418, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38297130

RESUMO

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.


Assuntos
Desidrocolesteróis , Ferroptose , Humanos , Membrana Celular/metabolismo , Colesterol/biossíntese , Colesterol/metabolismo , Sistemas CRISPR-Cas/genética , Desidrocolesteróis/metabolismo , Genoma Humano , Nefropatias/metabolismo , Membranas Mitocondriais/metabolismo , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Fosfolipídeos/metabolismo , Traumatismo por Reperfusão/metabolismo
2.
Brief Bioinform ; 23(1)2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-34905767

RESUMO

Clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology has become a popular tool for the study of genome function, and the use of this technology can achieve large-scale screening studies of specific phenotypes. Several analysis tools for CRISPR/Cas9 screening data have been developed, while high false positive rate remains a great challenge. To this end, we developed iCRISEE, an integrative analysis of CRISPR ScrEEn by reducing false positive hits. iCRISEE can dramatically reduce false positive hits and it is robust to different single guide RNA (sgRNA) library by introducing precise data filter and normalization, model selection and valid sgRNA number correction in data preprocessing, sgRNA ranking and gene ranking. Furthermore, a powerful web server has been presented to automatically complete the whole CRISPR/Cas9 screening analysis, where we integrated the main hypothesis in multiple algorithms as a full workflow, including quality control, sgRNA extracting, sgRNA alignment, sgRNA ranking, gene ranking and pathway enrichment. In addition, output of iCRISEE, including result mapping, sample clustering, sgRNA ranking and gene ranking, can be easily visualized and downloaded for publication. Taking together, iCRISEE presents to be the state-of-the-art and user-friendly tool for CRISPR screening data analysis. iCRISEE is available at https://www.icrisee.com.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Algoritmos , RNA Guia de Cinetoplastídeos/genética , RNA Guia de Cinetoplastídeos/metabolismo
3.
J Adv Res ; 63: 129-158, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39167629

RESUMO

BACKGROUND: Immunotherapy has emerged as a novel strategy for cancer treatment following surgery, radiotherapy, and chemotherapy. Immune checkpoint blockade and Chimeric antigen receptor (CAR)-T cell therapies have been successful in clinical trials. Cancer cells evade immune surveillance by hijacking inhibitory pathways via overexpression of checkpoint genes. The Cluster of Differentiation 47 (CD47) has emerged as a crucial checkpoint for cancer immunotherapy by working as a "don't eat me" signal and suppressing innate immune signaling. Furthermore, CD47 is highly expressed in many cancer types to protect cancer cells from phagocytosis via binding to SIRPα on phagocytes. Targeting CD47 by either interrupting the CD47-SIRPα axis or combing with other therapies has been demonstrated as an encouraging therapeutic strategy in cancer immunotherapy. Antibodies and small molecules that target CD47 have been explored in pre- and clinical trials. However, formidable challenges such as the anemia and palate aggregation cannot be avoided because of the wide presentation of CD47 on erythrocytes. AIM OF VIEW: This review summarizes the current knowledge on the regulation and function of CD47, and provides a new perspective for immunotherapy targeting CD47. It also highlights the clinical progress of targeting CD47 and discusses challenges and potential strategies. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review provides a comprehensive understanding of targeting CD47 in cancer immunotherapy, it also augments the concept of combination immunotherapy strategies by employing both innate and adaptive immune responses.


Assuntos
Antígeno CD47 , Imunoterapia , Neoplasias , Antígeno CD47/metabolismo , Antígeno CD47/imunologia , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Receptores Imunológicos/metabolismo , Receptores Imunológicos/imunologia , Animais , Transdução de Sinais , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação/metabolismo , Imunidade Inata , Fagocitose
4.
Adv Sci (Weinh) ; 11(12): e2301164, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38229144

RESUMO

Mechanistic target of rapamycin complex 1 (mTORC1) is a conserved serine/threonine kinase that integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activation requires tethering to lysosomes by the Ragulator-Rag complex. However, the dynamic regulation of the interaction between Ragulator and Rag guanosine triphosphatase (GTPase) remains unclear. In this study, that LAMTOR1, an essential component of Ragulator, is dynamically ubiquitinated depending on amino acid abundance is reported. It is found that the E3 ligase TRAF4 directly interacts with LAMTOR1 and catalyzes the K63-linked polyubiquitination of LAMTOR1 at K151. Ubiquitination of LAMTOR1 by TRAF4 promoted its binding to Rag GTPases and enhanced mTORC1 activation, K151R knock-in or TRAF4 knock-out blocks amino acid-induced mTORC1 activation and accelerates the development of inflammation-induced colon cancer. This study revealed that TRAF4-mediated LAMTOR1 ubiquitination is a regulatory mechanism for mTORC1 activation and provides a therapeutic target for diseases involving mTORC1 dysregulation.


Assuntos
Neoplasias Colorretais , Proteínas Monoméricas de Ligação ao GTP , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Fator 4 Associado a Receptor de TNF/metabolismo , Ubiquitinação , Aminoácidos/metabolismo
5.
Signal Transduct Target Ther ; 8(1): 104, 2023 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-36882399

RESUMO

Cancer immunotherapy, mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells, has revolutionized the oncology landscape as it utilizes patients' own immune systems in combating the cancer cells. Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes. Phagocytosis checkpoints, such as CD47, CD24, MHC-I, PD-L1, STC-1 and GD2, have emerged as essential checkpoints for cancer immunotherapy by functioning as "don't eat me" signals or interacting with "eat me" signals to suppress immune responses. Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy. Genetic ablation of these phagocytosis checkpoints, as well as blockade of their signaling pathways, robustly augments phagocytosis and reduces tumor size. Among all phagocytosis checkpoints, CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment. CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials. However, anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes. Here, we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy, highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.


Assuntos
Antígeno CD47 , Neoplasias , Humanos , Antígeno CD47/genética , Imunoterapia , Fagocitose/genética , Imunidade Inata/genética , Imunidade Adaptativa , Neoplasias/genética , Neoplasias/terapia
6.
Cell Death Differ ; 28(1): 139-155, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32678307

RESUMO

Ovarian cancer is the most lethal malignant tumor of female reproductive system. It is well-known that induction of STING-mediated type I interferons can enhance the resultant antitumor activity. However, STING pathway is usually inactivated in cancer cells at multiple levels. Here, we identified deubiquitinase USP35 is upregulated in ovarian cancer tissues. High level of USP35 was correlated with diminished CD8+ T cell infiltration and poor prognosis in ovarian cancer patients. Mechanistically, we found that silencing USP35 reinforces the activation of STING-TBK1-IRF3 pathway and promotes the expression of type I interferons. Our data further showed that USP35 can directly deubiquitinate and inactivate STING. Interestingly, activation of STING promotes its binding to USP35 in a STING phosphorylation-dependent manner. Functionally, we found that knockdown of USP35 sensitizes ovarian cancer cells to the DNA-damage chemotherapeutic drug cisplatin. Overall, our study indicates that upregulation of USP35 may be a mechanism of the restricted STING activity in cancer cells, and highlights the significance of USP35 as a potential therapeutic target for ovarian cancer.


Assuntos
Endopeptidases/metabolismo , Interferon Tipo I/metabolismo , Neoplasias Ovarianas/genética , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Endopeptidases/genética , Feminino , Humanos , Fator Regulador 3 de Interferon/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Cell ; 34(1): 103-118.e9, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-30008322

RESUMO

YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Núcleo Celular/enzimologia , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/enzimologia , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias Pulmonares/enzimologia , Fosfoproteínas/metabolismo , Processamento de Proteína Pós-Traducional , Células A549 , Transporte Ativo do Núcleo Celular , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular , Núcleo Celular/genética , Núcleo Celular/patologia , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HEK293 , Células HeLa , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Lisina , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfoproteínas/genética , Prognóstico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Fatores de Transcrição , Carga Tumoral , Proteínas de Sinalização YAP
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