A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade

Cell, Год журнала: 2018, Номер 175(4), С. 984 - 997.e24

Опубликована: Ноя. 1, 2018

Язык: Английский

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Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Cancer Cell, Год журнала: 2017, Номер 32(2), С. 204 - 220.e15

Опубликована: Авг. 1, 2017

Язык: Английский

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Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials

Signal Transduction and Targeted Therapy, Год журнала: 2020, Номер 5(1)

Опубликована: Сен. 23, 2020

Protein-protein interactions (PPIs) have pivotal roles in life processes. The studies showed that aberrant PPIs are associated with various diseases, including cancer, infectious and neurodegenerative diseases. Therefore, targeting is a direction treating diseases an essential strategy for the development of new drugs. In past few decades, modulation has been recognized as one most challenging drug discovery tasks. recent years, some modulators entered clinical studies, which approved marketing, indicating broad prospects. Here, we summarize advances modulators, small molecules, peptides, antibodies, hoping to provide guidance design novel drugs future.

Язык: Английский

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The MYC oncogene — the grand orchestrator of cancer growth and immune evasion

Nature Reviews Clinical Oncology, Год журнала: 2021, Номер 19(1), С. 23 - 36

Опубликована: Сен. 10, 2021

Язык: Английский

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The role of ubiquitination in tumorigenesis and targeted drug discovery

Signal Transduction and Targeted Therapy, Год журнала: 2020, Номер 5(1)

Опубликована: Фев. 29, 2020

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" "quality" various proteins, serving to ensure cell homeostasis guarantee life activities. The regulation ubiquitination is multifaceted works not only at transcriptional levels (phosphorylation, acetylation, methylation, etc.) but also level (activators or repressors). When regulatory mechanisms are aberrant, altered biological processes may induce serious human diseases, especially types cancer. In tumorigenesis, involve tumor metabolism, immunological microenvironment (TME), cancer stem (CSC) stemness so on. With regard some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc P53 significantly regulates activity mTORC1, AMPK PTEN-AKT signaling pathways. addition, TLR, RLR STING-dependent pathways modulates TME. Moreover, core regulator triplets (Nanog, Oct4 Sox2) members Wnt Hippo-YAP participates maintenance CSC stemness. Based on components, including proteasome, E3 ligases, E1, E2 deubiquitinases (DUBs), many molecular targeted drugs have been developed combat Among them, small molecule inhibitors targeting bortezomib, carfilzomib, oprozomib ixazomib, achieved tangible success. MLN7243 MLN4924 (targeting E1 enzyme), Leucettamol A CC0651 nutlin MI-219 compounds G5 F6 DUB activity) shown potential preclinical treatment. this review, we summarize latest progress understanding substrates for their special functions metabolism regulation, TME modulation maintenance. therapeutic targets reviewed, effects drugs.

Язык: Английский

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FBXW7: a critical tumor suppressor of human cancers

Molecular Cancer, Год журнала: 2018, Номер 17(1)

Опубликована: Авг. 7, 2018

The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014; Skaar JR Nat Rev Drug Discov 13:889-903, Nakayama KI K, 6:369-81, 2006). F-box WD repeat domain containing 7 (FBXW7), also known Sel10, hCDC4 or hAgo, a member the protein family, which functions substrate recognition component SCF E3 ubiquitin ligase. FBXW7 critical tumor suppressor one most commonly deregulated proteins human cancer. controls proteasome-mediated degradation oncoproteins cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch AURKA. Consistent with role FBXW7, it located at chromosome 4q32, genomic region deleted more than 30% all cancers (Spruck CH Res 62:4535-9, 2002). Genetic profiles based on high-throughput sequencing have revealed that frequently mutated cancers. In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, specific oncogenic signaling pathways can inactivate cancer cells. following sections, we will discuss regulation its oncogenesis, clinical implications prognostic value loss function

Язык: Английский

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Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element

Cell, Год журнала: 2018, Номер 173(6), С. 1398 - 1412.e22

Опубликована: Май 1, 2018

Язык: Английский

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lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

Cancer Cell, Год журнала: 2018, Номер 33(4), С. 706 - 720.e9

Опубликована: Апрель 1, 2018

We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation 1,006 lncRNA including EPIC1 (epigenetically-induced lncRNA1). Overexpression is associated with poor prognosis luminal B breast patients enhances tumor growth vitro vivo. Mechanistically, promotes cell-cycle progression by interacting MYC through EPIC1's 129–283 nt region. knockdown reduces occupancy its target (e.g., CDKN1A, CCNA2, CDC20, CDC45). depletion abolishes regulation tumorigenesis

Язык: Английский

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Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Cell Systems, Год журнала: 2018, Номер 6(3), С. 282 - 300.e2

Опубликована: Март 1, 2018

Highlights•MYC paralogs are significantly amplified (28% of all samples)•MYC antagonists mutated (MGA, 4% samples) or deleted (MNT, 10% alterations mutually exclusive with PIK3CA, PTEN, APC, BRAF alterations•Expression analysis reveals pan-cancer and tumor-specific MYC-associated pathwaysSummaryAlthough the MYC oncogene has been implicated in cancer, a systematic assessment MYC, related transcription factors, co-regulatory proteins, forming proximal network (PMN), across human cancers is lacking. Using computational approaches, we define genomic proteomic features associated PMN 33 The Cancer Genome Atlas. Pan-cancer, 28% samples had at least one amplified. In contrast, MGA MNT were most frequently members, proposing role as tumor suppressors. alterations, suggesting that distinct oncogenic driver. Expression revealed pathways subtypes, such immune response growth factor signaling; chromatin, translation, DNA replication/repair conserved pan-cancer. This insights into biology reference for biomarkers therapeutics PMN.Graphical abstract

Язык: Английский

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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis

Science, Год журнала: 2018, Номер 360(6390), С. 800 - 805

Опубликована: Апрель 5, 2018

Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing RNA], a method quantification newly synthesized messenger RNAs (mRNAs), with pharmacological chemical-genetic perturbation order define functions two transcriptional hubs cancer, BRD4 MYC, interrogate responses BET bromodomain inhibitors (BETis). found that acts as general coactivator RNA polymerase II-dependent transcription, which broadly repressed upon high-dose BETi treatment. At doses triggering selective effects leukemia, BETis deregulate small set hypersensitive including MYC. In contrast BRD4, MYC primarily activator controlling processes such ribosome biogenesis de novo purine synthesis. Our study establishes simple scalable strategy identify any gene or pathway.

Язык: Английский

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