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| Open AccessMulti-layered proteomic analyses decode compositional and functional effects of cancer mutations on kinase complexes
Diseases can be associated with various mutations of the same gene, but the molecular consequences of specific mutations remain incompletely understood. Here, the authors present an integrated proteomic workflow to determine the molecular response of cells to different cancer-associated mutations of the kinase Dyrk2.
- Martin Mehnert
- , Rodolfo Ciuffa
- & Ruedi Aebersold
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Article
| Open AccessChronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation
It is unclear how resident p16-expressing senescent cells affect the propensity of tissues to develop cancer. Here, the authors show that chronic p16 expression in the mouse epidermis causes hyperplasia and dysplasia through Wnt-mediated paracrine stimulation of proliferating keratinocytes, and can contribute to tumour formation.
- Narmen Azazmeh
- , Benjamin Assouline
- & Ittai Ben-Porath
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Article
| Open AccessYAP1/TAZ drives ependymoma-like tumour formation in mice
YAP1 gene fusions are found in subgroups of paediatric ependymomas. Here the authors show that YAP1 activation in NeuroD6 positive neuronal precursor cells can induce ependymoma-like tumours in mice.
- Noreen Eder
- , Federico Roncaroli
- & Sila K. Ultanir
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Article
| Open AccessLoss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties
Both gain-of-function of mutant p53 (GOF) and loss of wild-type p53 (LOH) are independently associated with cancer. Here, the authors show that LOH promotes GOF tumourigenesis by increasing tumor-initiating ability and metastasis.
- Mizuho Nakayama
- , Chang Pyo Hong
- & Masanobu Oshima
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Article
| Open AccessEffective combinatorial immunotherapy for penile squamous cell carcinoma
Penile squamous cell carcinoma (PSCC) is a cancer that is associated with significant mortality. Here, the authors develop a mouse model of PSCC by co-deletion of Smad4 and Apc in the androgen-responsive penile epithelium, and show synergistic efficacy of checkpoint therapy with cabozantinib or celecoxib in their model.
- Tianhe Huang
- , Xi Cheng
- & Xin Lu
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Article
| Open AccessProper chromosome alignment depends on BRCA2 phosphorylation by PLK1
The BRCA2 tumour suppressor protein is known to play an important role in homologous recombination. Here the authors reveal how the phosphorylation of BRCA2 by Polo-like kinase 1 (PLK1) contributes to the regulation of mitosis.
- Åsa Ehlén
- , Charlotte Martin
- & Aura Carreira
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Article
| Open AccessFBXO22 degrades nuclear PTEN to promote tumorigenesis
Loss of nuclear PTEN is associated with aggressive cancers. Here the authors show that nuclear PTEN is more susceptible to ubiquitin-mediated proteasomal degradation than cytoplasmic PTEN, and identify FBXO22 ubiquitinates and degrades nuclear PTEN to promote tumorigenesis.
- Meng-Kai Ge
- , Na Zhang
- & Shao-Ming Shen
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Article
| Open AccessCancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours
The growth of cancer cells can be stably arrested by cytokine-induced senescence. Here, the authors show that cancers with defects in senescence-inducing cell cycle regulator pathways are resistant to immune checkpoint blockade.
- Ellen Brenner
- , Barbara F. Schörg
- & Martin Röcken
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Article
| Open AccessC/EBPɑ is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition
In breast cancer TGF-β regulates C/EBPα and can induce epithelial-to-mesenchymal transition (EMT). Here, the authors show that C/EBPα maintains epithelial homeostasis and prevents EMT-mediated tumorigenesis.
- Ana Rita Lourenço
- , M. Guy Roukens
- & Paul J. Coffer
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Article
| Open AccessLRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer
LRIG1 is a tumour suppressor in several cancers. Here, the authors show that androgen receptor directly transactivates LRIG1 which then antagonises ERBB signalling and c-Myc expression to inhibit prostate tumorigenesis.
- Qiuhui Li
- , Bigang Liu
- & Dean G. Tang
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Article
| Open AccessIdentification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network
There is disproportionally high cancer prevalence in males. Here, the authors analyse the tumour suppressor p53 in sporadic cancers, highlighting a higher incidence of its mutation in males. Males are further disadvantaged by a failure to shield against the expression of damaged X-linked genes in p53-networks. These factors likely contribute to sex-disparity.
- Sue Haupt
- , Franco Caramia
- & Ygal Haupt
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Article
| Open AccessZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer
High-grade serous ovarian cancers (HGSOCs) have defects in homologous recombination despite a lack of BRCA1/2 mutations. Here, the authors show that ZC3H18 positively regulates BRCA1 transcription and its loss causes BRCA1 promoter methylation and increased HR deficiency in HGSOCs.
- Arun Kanakkanthara
- , Catherine J. Huntoon
- & Larry M. Karnitz
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Article
| Open AccessCaspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis
Caspases are most closely associated with cell death, but many have other cellular functions. Here, Das et al. find that upon metabolic stress, caspase-10 cleaves ACLY to regulate metabolic homeostasis and epigenetic reprogramming by altering Acetyl-CoA levels.
- Rajni Kumari
- , Ruhi S. Deshmukh
- & Sanjeev Das
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Article
| Open AccessInterplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis
The Anaphase Promoting Complex adaptor protein Cdh1 tightly controls cell cycle progression to restrain tumorigenesis but the mechanism is not completely known. Here, the authors show that reciprocal inhibition between Cdh1 and the c-Src signaling pathway regulate breast cancer tumorigenesis.
- Tao Han
- , Shulong Jiang
- & Lixin Wan
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Article
| Open AccessInactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions
OPCML is a tumour suppressor gene that is epigenetically silenced in ovarian cancer and is somatically mutated in various cancers. Here, the authors solve the X-ray crystal structure of OPCML and model clinically relevant mutations that could contribute to tumorigenesis.
- James R. Birtley
- , Mohammad Alomary
- & Hani Gabra
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Article
| Open AccessInhibition of MYC by the SMARCB1 tumor suppressor
SMARCB1/SNF5 is a tumour suppressor and component of the SWI/SNF chromatin remodeler. Here the authors show that, independent of chromatin remodelling activities, SNF5 acts to inhibit the pro-tumorigenic transcriptional program of MYC via control of RNA polymerase pause release at MYC target genes.
- April M. Weissmiller
- , Jing Wang
- & William P. Tansey
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Article
| Open AccessGasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation
Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.
- Corey Rogers
- , Dan A. Erkes
- & Emad S. Alnemri
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Article
| Open AccessIdentification of the kinase STK25 as an upstream activator of LATS signaling
Hippo pathway inactivation plays a role in many cancers, although how tumor cells depress signaling is unclear. Here, Lim et al. identify STK25, which activates LATS in a manner distinct from other upstream kinases and is focally deleted from a range of human cancers.
- Sanghee Lim
- , Nicole Hermance
- & Neil J. Ganem
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Article
| Open AccessPTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression
PTEN is a lipid phosphatase that functions as a dose-dependent tumor suppressor through the PI3K/AKT pathway. Here the authors describe a signaling feedback mechanism where PTEN stability is regulated through transcriptional upregulation of X-linked ubiquitin-specific protease 11 (USP11) via the PI3K/FOXO pathway.
- Mi Kyung Park
- , Yixin Yao
- & Min Sup Song
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Article
| Open AccessWDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation
Overexpression of RAS proteins is frequently observed in patients with hepatocellular carcinoma. Here, the authors identify an HRAS binding protein, the E3 ubiquitin ligase WDR76, which promotes HRAS degradation, thus functioning as a tumour suppressor in liver cancer
- Woo-Jeong Jeong
- , Jong-Chan Park
- & Kang-Yell Choi
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Article
| Open AccessRETRACTED ARTICLE: Mir20a/106a-WTX axis regulates RhoGDIa/CDC42 signaling and colon cancer progression
Wilms tumor gene on the X chromosome (WTX) is commonly downregulated in human cancers. Here the authors show that in colorectal cancer (CRC) WTX expression is downregulated via miR20a and miR160a and its loss promotes tumor development and liver metastasis by disrupting the interaction between RhoGDIα and CDC42 leading to the activation of the CDC42 downstream cascades.
- Gui-fang Zhu
- , Yang-wei Xu
- & Qing-ling Zhang
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Article
| Open AccessSingle cell RNA-sequencing identifies a metabolic aspect of apoptosis in Rbf mutant
The function of the Retinoblastoma (Rb) protein is regulated by its cellular environment. Here, the authors perform single cell RNA-sequencing during Drosophila eye development and identify the impact of an Rbf mutation, which sensitises specific cells to apoptosis by changing metabolism.
- Majd M. Ariss
- , Abul B. M. M. K. Islam
- & Maxim V. Frolov
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Article
| Open AccessMonoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1
Additional sex combs-like (ASXLs) stimulate BAP1 deubiquitinase activity to induce tumor suppression, but how these complexes work in coordination in vivo is unclear. Here, the authors show the mutually reinforcing roles of BAP1 and ASXLs such that BAP1 promotes DEUBAD monoubiquitination of ASXL2, which in turn stimulates BAP1 DUB activity.
- Salima Daou
- , Haithem Barbour
- & El Bachir Affar
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Article
| Open AccessLoss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis
In breast cancer, the loss of expression of WW domain-containing oxireductase (Wwox) has been observed. Here, the authors illustrate that in triple negative breast cancer models Wwox suppresses metastasis and proliferation via the JAK2/STAT3 pathway.
- Renxu Chang
- , Lele Song
- & Lixing Zhan
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Article
| Open AccessLgl1 controls NG2 endocytic pathway to regulate oligodendrocyte differentiation and asymmetric cell division and gliomagenesis
Oligodendrocyte progenitor cells (OPCs) undergo asymmetric cell division, and disruption of such mechanism can generate oligodendroglioma precursors. Here, Daynac and colleagues show that Lgl1 regulates asymmetric division and differentiation of OPCs by interfering with the endocytosis pathway, and that Lgl1 knockout can lead to gliomagenesis.
- Mathieu Daynac
- , Malek Chouchane
- & Claudia K. Petritsch
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Article
| Open AccessUTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma
UTX is a tumor suppressor gene located on the X-chromosome so it could potentially contribute to the cancer gender bias. Here the authors, using a mouse model of B cell lymphoma, show that UTX is a dosage sensitive tumor suppressor and may be responsible for some of the increased incidence and possibly aggressiveness of male cancers that harbour UTX mutations.
- Xiaoxi Li
- , Yanli Zhang
- & Hai Jiang
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Article
| Open AccessNuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role
Cytoplasmic PTEN is a tumor suppressor that antagonises PI3K signalling. Here, the authors show that nuclear PTEN can interact with the spliceosomal proteins and drive pre-mRNA splicing in a phosphatase-independent manner, in particular, PTEN depletion promotes Golgi extension and secretion through GOLGA2 exon skipping.
- Shao-Ming Shen
- , Yan Ji
- & Guo-Qiang Chen
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Article
| Open AccessThe genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma
Glioblastoma can be classified based on IDH and TERT promoter mutations, but ~20% of glioblastoma do not have these mutations (TERTpWT-IDHWT glioblastoma). Here, the authors present a genetic landscape of TERTpWT-IDHWT glioblastoma, identifying a telomerase-positive subgroup driven by TERT-structural rearrangements and an ALT-positive subgroup with mutations in ATRX or SMARCAL1.
- Bill H. Diplas
- , Xujun He
- & Hai Yan
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Article
| Open AccessUSP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells
Gain-of-function mutants of p53 are important for cancer development and strategies to target specifically these isoforms are being investigated. Here the authors report that USP15 is a deubiquitinase specifically regulating p53-R175H levels that can be targeted by a small molecule.
- Achuth Padmanabhan
- , Nicholes Candelaria
- & JoAnne S. Richards
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Article
| Open Access∆133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling
Aberrant expression of the Δ133p53 isoform is linked to many cancers. Here, the authors utilise a model of the Δ133p53 isoform that is prone to tumours and inflammation, showing that Δ133p53 promotes tumour cell invasion by activation of the JAK-STAT and RhoA-ROCK pathways in an IL-6 dependent manner.
- Hamish Campbell
- , Nicholas Fleming
- & Antony W. Braithwaite
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Article
| Open AccessMethylation-regulated decommissioning of multimeric PP2A complexes
Protein phosphatase 2A (PP2A) forms different holoenzymes but little is known about the disassembly of these important signalling complexes. Here the authors present the crystal structure of PP2A bound to TOR signaling pathway regulator (TIPRL) and give insights into the methylation-dependent disassembly of PP2A holenzymes.
- Cheng-Guo Wu
- , Aiping Zheng
- & Yongna Xing
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Article
| Open AccessPEPD is a pivotal regulator of p53 tumor suppressor
p53 is a pivotal tumour suppressor that is activated by various cellular stress inducers. Here, the authors show that peptidase D (PEPD) promotes the growth of cancer cells by suppressing p53 and that the complex PEPD-p53 is critical for robust p53 activation in response to stress signals.
- Lu Yang
- , Yun Li
- & Yuesheng Zhang
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Article
| Open AccessNotch transactivates Rheb to maintain the multipotency of TSC-null cells
Tuberous sclerosis complex (TSC) is a rare genetic condition causing tumours with differentiation abnormalities; however the molecular mechanisms causing these defects are unclear. Here the authors show that Notch cooperates with Rheb to block cell differentiation forming a regulatory loop that could underlie TSC tumorigenesis.
- Jun-Hung Cho
- , Bhaumik Patel
- & Magdalena Karbowniczek
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Article
| Open AccessParkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression
Parkin is an E3 ubiquitin ligase involved in Parkinson’s disease. Parkin has also been linked to cancer suppression but the mechanisms are unclear. Here the authors show that Parkin regulates HIF-1α through ubiquitin-dependent degradation, thus inhibiting metastasis of breast cancer cells.
- Juan Liu
- , Cen Zhang
- & Zhaohui Feng
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Article
| Open AccessPTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer
PTEN is often lost in prostate cancer. In this study, the authors show that PTEN can act as a protein phosphatase that targets active PTK6, thereby regulating its oncogenic signaling in prostate cancer progression.
- Darren J. Wozniak
- , Andre Kajdacsy-Balla
- & Angela L. Tyner
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Article
| Open AccessHit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors
“Although aberrant promoter DNA hypermethylation is a hallmark of cancer, it is not clear whether it is sufficient to drive transformation. Here, the authors use CRISPR-dCas9 to perform hit-and-run epigenetic editing, which prevents senescence entry in primary breast cells from healthy donors.”
- Emily A. Saunderson
- , Peter Stepper
- & Gabriella Ficz
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Article
| Open AccessStable MOB1 interaction with Hippo/MST is not essential for development and tissue growth control
The Hippo tumor suppressor pathway is essential for development and tissue growth control. Here the authors employ a multi-disciplinary approach to characterize the interactions of the three Hippo kinases with the signaling adaptor MOB1 and show how they differently affect development, tissue growth and tumor suppression.
- Yavuz Kulaberoglu
- , Kui Lin
- & Alexander Hergovich
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Article
| Open AccessLive-cell p53 single-molecule binding is modulated by C-terminal acetylation and correlates with transcriptional activity
Both transcription binding kinetics and post-translational modifications of transcription factors are thought to play a role in the modulation of transcription. Here the authors use single-molecule tracking to directly demonstrate that p53 acetylation modulates promoter residence time and transcriptional activity.
- Alessia Loffreda
- , Emanuela Jacchetti
- & Davide Mazza
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Article
| Open AccessTiming of Smarcb1 and Nf2 inactivation determines schwannoma versus rhabdoid tumor development
SMARCB1 mutations predispose to rhabdoid tumors and schwannomas but the mechanisms underlying the tumor type specificity are unknown. Here the authors present new mouse models and show that early Smarcb1 loss causes rhabdoid tumors whereas loss at later stages combined with Nf2 gene inactivation causes shwannomas.
- Jeremie Vitte
- , Fuying Gao
- & Marco Giovannini
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Article
| Open AccessNegative regulation of EGFR signalling by the human folliculin tumour suppressor protein
Folliculin is a known tumour suppressor but the molecular mechanisms behind this function are unclear. Here the authors show that Folliculin regulates EGFR signalling by modulating its Rab7a-dependent trafficking.
- Laura A. Laviolette
- , Julien Mermoud
- & Othon Iliopoulos
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Article
| Open AccessMembrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression
LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Here the authors show that LKB1 activation requires direct binding to phospholipids and show this has an implication for carcinogenesis.
- Giada Dogliotti
- , Lars Kullmann
- & Michael P. Krahn
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Article
| Open AccessInhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation
Efficient therapeutic strategies to target mutant-p53 cancers are needed. Here, the authors demonstrate the molecular mechanism through which mutant-p53 tumours are susceptible to oxidative damage and propose a potential strategy for targeting such cancers by inhibiting the SLC7A11-glutathione axis.
- David S. Liu
- , Cuong P. Duong
- & Nicholas J. Clemons
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Article
| Open AccessMAX inactivation is an early event in GIST development that regulates p16 and cell proliferation
In gastrointestinal stromal tumours early mutations in known genes are frequently followed by chromosome 14q deletion. Here the authors find mutations resulting in loss of MAX protein expression conserved between primary tumours and metastases in the same patients, suggesting thatMAXmutation is an early event.
- Inga-Marie Schaefer
- , Yuexiang Wang
- & Jonathan A. Fletcher
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Article
| Open AccessMutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma
Kras activation and p16 inactivation cooperatively promote pancreatic cancer progression. Here, the authors show that such cooperation depends upon an increased expression of the NAD(P)H oxidase NOX4 achieved through transcription factors independently regulated by the two oncogenic genetic alterations.
- Huai-Qiang Ju
- , Haoqiang Ying
- & Paul J. Chiao
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Article
| Open AccessInduced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours
Several breast cancers may originate from mammary luminal cells and inactivating mutations of p53 are present in most triple-negative breast cancers. Here, the authors show that loss of p53 from luminal cells in mice results in their clonal expansion and mammary tumour formation.
- Luwei Tao
- , Dongxi Xiang
- & Zhe Li
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Article
| Open AccessHOPX hypermethylation promotes metastasis via activating SNAIL transcription in nasopharyngeal carcinoma
HOPX is a transcription factor epigenetically silenced in several cancers. Here the authors, by analysing methylation profiles, identify HOPX as a suppressor of metastasis in nasopharyngeal carcinoma: mechanistically HOPX inhibitsSNAILtranscription through deacetylation-mediated silencing.
- Xianyue Ren
- , Xiaojing Yang
- & Jun Ma
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Article
| Open AccessThe β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor
F-box proteins β-TrCP1 and SKP2 act as oncogenes by promoting targeted degradation of critical protein substrates. Here, the authors identify an axis of F-box proteins β-TrCP1-FBXW2-SKP2 where FBXW2 is a substrate of β-TrCP1 but mediates the degradation of SKP2, thus acting as a tumour suppressor.
- Jie Xu
- , Weihua Zhou
- & Yi Sun
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Article
| Open AccessPleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53
p53 is an oncosuppressor regulating several genes at the transcriptional level. Here, the authors identify a negative feedback loop between PHLDB3 and p53; PHLDB3 is a transcriptional target of p53 which facilitates MDM2-mediated p53 ubiquitination and degradation, impacting on tumorigenesis.
- Tengfei Chao
- , Xiang Zhou
- & Hua Lu
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Article
| Open AccessThe tumour suppressor CYLD regulates the p53 DNA damage response
CYLD is a deubiquitinase known to act as a tumour suppressor in different models of carcinogenesis. Here, the authors show that CYLD suppresses carcinogen-induced tumorigenesis by deubiquitinating p53 and promoting its stabilization and activation in response to DNA damage.
- Vanesa Fernández-Majada
- , Patrick-Simon Welz
- & Manolis Pasparakis