Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway.

Abstract:

:Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation by the CBP and p300 transcriptional coactivators. Through a target-based high-throughput screen, we identified chetomin as a disrupter of HIF binding to p300. At a molecular level, chetomin disrupts the structure of the CH1 domain of p300 and precludes its interaction with HIF, thereby attenuating hypoxia-inducible transcription. Systemic administration of chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth. These results demonstrate a therapeutic window for pharmacological attenuation of HIF activity and further establish the feasibility of disrupting a signal transduction pathway by targeting the function of a transcriptional coactivator with a small molecule.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Kung AL,Zabludoff SD,France DS,Freedman SJ,Tanner EA,Vieira A,Cornell-Kennon S,Lee J,Wang B,Wang J,Memmert K,Naegeli HU,Petersen F,Eck MJ,Bair KW,Wood AW,Livingston DM

doi

10.1016/j.ccr.2004.06.009

keywords:

subject

Has Abstract

pub_date

2004-07-01 00:00:00

pages

33-43

issue

1

eissn

1535-6108

issn

1878-3686

pii

S153561080400176X

journal_volume

6

pub_type

杂志文章
  • Targeting oxidative stress in embryonal rhabdomyosarcoma.

    abstract::Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and c...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2013.11.002

    authors: Chen X,Stewart E,Shelat AA,Qu C,Bahrami A,Hatley M,Wu G,Bradley C,McEvoy J,Pappo A,Spunt S,Valentine MB,Valentine V,Krafcik F,Lang WH,Wierdl M,Tsurkan L,Tolleman V,Federico SM,Morton C,Lu C,Ding L,Easton J,R

    更新日期:2013-12-09 00:00:00

  • CD103+ dendritic cells producing interleukin-12 in anticancer immunosurveillance.

    abstract::The mechanisms through which tumor antigen-specific T cells are elicited in natural or chemotherapy-induced immunosurveillance have been elusive. In this issue of Cancer Cell, two papers by Broz and colleagues and Ruffell and colleagues delineate an important role for a specific dendritic cell subset characterized by ...

    journal_title:Cancer cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.ccell.2014.10.008

    authors: Zitvogel L,Kroemer G

    更新日期:2014-11-10 00:00:00

  • Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability.

    abstract::In this study, we show that the formation of polyploidy following sustained mitotic checkpoint activation appears to be preceded by the ubiquitin-dependent proteolysis of hBubR1. In addition, the level of hBubR1 is significantly reduced not only in polyploid cells created by sustained mitotic spindle damage, but also ...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/s1535-6108(03)00302-7

    authors: Shin HJ,Baek KH,Jeon AH,Park MT,Lee SJ,Kang CM,Lee HS,Yoo SH,Chung DH,Sung YC,McKeon F,Lee CW

    更新日期:2003-12-01 00:00:00

  • Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma.

    abstract::Our understanding of Ewing's sarcoma development mediated by the EWS/FLI fusion protein has been limited by a lack of knowledge regarding the tumor cell of origin. To circumvent this, we analyzed the function of EWS/FLI in Ewing's sarcoma itself. By combining retroviral-mediated RNA interference with reexpression stud...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2006.04.004

    authors: Smith R,Owen LA,Trem DJ,Wong JS,Whangbo JS,Golub TR,Lessnick SL

    更新日期:2006-05-01 00:00:00

  • ROR1C Regulates Differentiation of Myeloid-Derived Suppressor Cells.

    abstract::Myeloid-derived suppressor cells (MDSCs) play a major role in cancer. MDSC expansion is closely associated with tumor progression, but molecular mechanisms of this expansion remain poorly understood. In this issue of Cancer Cell, Strauss and colleagues describe the roles of the nuclear receptor ROR1C in the regulation...

    journal_title:Cancer cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.ccell.2015.07.007

    authors: Gabrilovich D,Nefedova Y

    更新日期:2015-08-10 00:00:00

  • Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations.

    abstract::The SH2-containing tyrosine phosphatase Shp2 (PTPN11) is required for growth factor and cytokine signaling. Germline Shp2 mutations cause Noonan Syndrome (NS), which is associated with increased risk of juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations occur in sporadic JMML and other leukemias. We found...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2005.01.010

    authors: Mohi MG,Williams IR,Dearolf CR,Chan G,Kutok JL,Cohen S,Morgan K,Boulton C,Shigematsu H,Keilhack H,Akashi K,Gilliland DG,Neel BG

    更新日期:2005-02-01 00:00:00

  • Kidney cancer: now available in a new flavor.

    abstract::The role of the von Hippel-Lindau tumor suppressor protein (pVHL) in kidney cancer has provided a rationale for treating this disease with hypoxia-inducible factor (HIF) antagonists. In this issue, Simon and coworkers show that the molecular signature of VHL(-/-) kidney cancers is profoundly influenced by whether they...

    journal_title:Cancer cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.ccr.2008.11.005

    authors: Kaelin WG Jr

    更新日期:2008-12-09 00:00:00

  • Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.

    abstract::Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccell.2014.11.019

    authors: Harris IS,Treloar AE,Inoue S,Sasaki M,Gorrini C,Lee KC,Yung KY,Brenner D,Knobbe-Thomsen CB,Cox MA,Elia A,Berger T,Cescon DW,Adeoye A,Brüstle A,Molyneux SD,Mason JM,Li WY,Yamamoto K,Wakeham A,Berman HK,Khokha R,

    更新日期:2015-02-09 00:00:00

  • Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo.

    abstract::A key characteristic of stem cells and cancer cells is their ability to self-renew. To test if Wnt signaling can regulate the self-renewal of both stem cells and cancer cells in the hematopoietic system, we developed mice that lack beta-catenin in their hematopoietic cells. Here we show that beta-catenin-deficient mic...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2007.11.003

    authors: Zhao C,Blum J,Chen A,Kwon HY,Jung SH,Cook JM,Lagoo A,Reya T

    更新日期:2007-12-01 00:00:00

  • Optimal gene expression analysis by microarrays.

    abstract::DNA microarrays make possible the rapid and comprehensive assessment of the transcriptional activity of a cell, and as such have proven valuable in assessing the molecular contributors to biological processes and in the classification of human cancers. The major challenge in using this technology is the analysis of it...

    journal_title:Cancer cell

    pub_type: 杂志文章,评审

    doi:10.1016/s1535-6108(02)00181-2

    authors: Miller LD,Long PM,Wong L,Mukherjee S,McShane LM,Liu ET

    更新日期:2002-11-01 00:00:00

  • Nuclear factor-kappaB: the enemy within.

    abstract::Numerous lines of investigation suggest that nuclear factor NF-kappaB, a proinflammatory transcription factor, could promote tumorigenesis. Various inflammatory agents, carcinogens, tumor promoters, and the tumor microenvironment activate NF-kappaB. NF-kappaB proteins themselves and proteins regulated by it have been ...

    journal_title:Cancer cell

    pub_type: 杂志文章,评审

    doi:10.1016/j.ccr.2004.09.003

    authors: Aggarwal BB

    更新日期:2004-09-01 00:00:00

  • Strategies for p53 reactivation in human sarcoma.

    abstract::Emerging strategies in cancer therapeutics link the genomic mutational and proteomic landscape, allowing intelligent reasoning on target selection. In this issue of Cancer Cell, Piccinin and colleagues use this approach to demonstrate that the mesenchymal protein Twist1 inhibits p53, providing a novel target for react...

    journal_title:Cancer cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.ccr.2012.08.020

    authors: Hupp TR,Hayward RL,Vojtesek B

    更新日期:2012-09-11 00:00:00

  • HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity.

    abstract::HIF-2alpha promotes von Hippel-Lindau (VHL)-deficient renal clear cell carcinoma (RCC) tumorigenesis, while HIF-1alpha inhibits RCC growth. As HIF-1alpha antagonizes c-Myc function, we hypothesized that HIF-2alpha might enhance c-Myc activity. We demonstrate here that HIF-2alpha promotes cell-cycle progression in hypo...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2007.02.006

    authors: Gordan JD,Bertout JA,Hu CJ,Diehl JA,Simon MC

    更新日期:2007-04-01 00:00:00

  • β-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas.

    abstract::Malignant melanoma is characterized by frequent metastasis, however, specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating β-catenin le...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2011.10.030

    authors: Damsky WE,Curley DP,Santhanakrishnan M,Rosenbaum LE,Platt JT,Gould Rothberg BE,Taketo MM,Dankort D,Rimm DL,McMahon M,Bosenberg M

    更新日期:2011-12-13 00:00:00

  • Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.

    abstract::Inactivation of the von Hippel-Lindau tumor suppressor gene is linked to the development of hereditary (VHL Disease-associated) and sporadic clear cell carcinoma of the kidney. The VHL gene product, pVHL, targets the heterodimeric transcription factor HIF for polyubiquitination, and restoration of pVHL function in VHL...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/s1535-6108(02)00043-0

    authors: Kondo K,Klco J,Nakamura E,Lechpammer M,Kaelin WG Jr

    更新日期:2002-04-01 00:00:00

  • Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway.

    abstract::Molecular mechanisms associated with tumor metastasis remain poorly understood. Here we report that acquired expression of periostin by colon cancer cells greatly promoted metastatic development of colon tumors. Periostin is overexpressed in more than 80% of human colon cancers examined with highest expression in meta...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/s1535-6108(04)00081-9

    authors: Bao S,Ouyang G,Bai X,Huang Z,Ma C,Liu M,Shao R,Anderson RM,Rich JN,Wang XF

    更新日期:2004-04-01 00:00:00

  • Kit-activating mutations cooperate with Spi-1/PU.1 overexpression to promote tumorigenic progression during erythroleukemia in mice.

    abstract::The erythroleukemia developed by spi-1/PU.1 transgenic mice is a multistage process characterized by an early arrest of the proerythroblast differentiation followed later on by malignant transformation. Herein, we report the presence of acquired mutations in the SCF receptor gene (Kit) in 86% of tumors isolated during...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2005.11.009

    authors: Kosmider O,Denis N,Lacout C,Vainchenker W,Dubreuil P,Moreau-Gachelin F

    更新日期:2005-12-01 00:00:00

  • Tumor type-dependent function of the par3 polarity protein in skin tumorigenesis.

    abstract::Cell polarization is crucial during development and tissue homeostasis and is regulated by conserved proteins of the Scribble, Crumbs, and Par complexes. In mouse skin tumorigenesis, Par3 deficiency results in reduced papilloma formation and growth. Par3 mediates its tumor-promoting activity through regulation of grow...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2012.08.004

    authors: Iden S,van Riel WE,Schäfer R,Song JY,Hirose T,Ohno S,Collard JG

    更新日期:2012-09-11 00:00:00

  • The HECT family of E3 ubiquitin ligases: multiple players in cancer development.

    abstract::The involvement of the homologous to E6-AP carboxyl terminus (HECT)-type E3s in crucial signaling pathways implicated in tumorigenesis is presently an area of intense research and extensive scientific interest. This review highlights recent discoveries on the ubiquitin-mediated degradation of crucial tumor suppressor ...

    journal_title:Cancer cell

    pub_type: 杂志文章,评审

    doi:10.1016/j.ccr.2008.06.001

    authors: Bernassola F,Karin M,Ciechanover A,Melino G

    更新日期:2008-07-08 00:00:00

  • The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.

    abstract::Tumors constitute highly suppressive microenvironments in which infiltrating T cells are "exhausted" by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human an...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccell.2014.10.018

    authors: Johnston RJ,Comps-Agrar L,Hackney J,Yu X,Huseni M,Yang Y,Park S,Javinal V,Chiu H,Irving B,Eaton DL,Grogan JL

    更新日期:2014-12-08 00:00:00

  • It's the peptide-MHC affinity, stupid.

    abstract::Adoptively transferred T cells can reject large established tumors, but recurrence due to escape variants frequently occurs. In this issue of Cancer Cell, Engels et al. demonstrate that the affinity of the target peptide to the MHC molecule determines whether large tumors will relapse following adoptive T cell therapy...

    journal_title:Cancer cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.ccr.2013.04.004

    authors: Kammertoens T,Blankenstein T

    更新日期:2013-04-15 00:00:00

  • A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2.

    abstract::Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. Here, we identify and validate a prognostic gene expression signature correlating with survival in a series of microdissect...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2009.10.018

    authors: Mok SC,Bonome T,Vathipadiekal V,Bell A,Johnson ME,Wong KK,Park DC,Hao K,Yip DK,Donninger H,Ozbun L,Samimi G,Brady J,Randonovich M,Pise-Masison CA,Barrett JC,Wong WH,Welch WR,Berkowitz RS,Birrer MJ

    更新日期:2009-12-08 00:00:00

  • ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5.

    abstract::MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation b...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccell.2016.10.001

    authors: Sun HL,Cui R,Zhou J,Teng KY,Hsiao YH,Nakanishi K,Fassan M,Luo Z,Shi G,Tili E,Kutay H,Lovat F,Vicentini C,Huang HL,Wang SW,Kim T,Zanesi N,Jeon YJ,Lee TJ,Guh JH,Hung MC,Ghoshal K,Teng CM,Peng Y,Croce CM

    更新日期:2016-11-14 00:00:00

  • RalGDS is required for tumor formation in a model of skin carcinogenesis.

    abstract::To investigate the role of signaling by the small GTPase Ral, we have generated mice deficient for RalGDS, a guanine nucleotide exchange factor that activates Ral. We show that RalGDS is dispensable for mouse development but plays a substantial role in Ras-induced oncogenesis. Lack of RalGDS results in reduced tumor i...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2005.01.029

    authors: González-García A,Pritchard CA,Paterson HF,Mavria G,Stamp G,Marshall CJ

    更新日期:2005-03-01 00:00:00

  • Advancing the field of drug delivery: taking aim at cancer.

    abstract::Drug delivery systems for cancer therapeutics have now been used by millions of patients and have resulted in the creation of new therapies as well as significantly improving existing ones. Here we discuss a number of the drug delivery systems that have been approved by regulatory authorities and that are currently in...

    journal_title:Cancer cell

    pub_type: 杂志文章,评审

    doi:10.1016/s1535-6108(03)00276-9

    authors: Moses MA,Brem H,Langer R

    更新日期:2003-11-01 00:00:00

  • Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model.

    abstract::Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell (or cells) of origin has not been rigorously determined. We previously reported mouse models based on conditional inactivation of the human astrocytoma-relevant tumor suppressors p53,...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2008.12.006

    authors: Alcantara Llaguno S,Chen J,Kwon CH,Jackson EL,Li Y,Burns DK,Alvarez-Buylla A,Parada LF

    更新日期:2009-01-06 00:00:00

  • Elevated CXorf67 Expression in PFA Ependymomas Suppresses DNA Repair and Sensitizes to PARP Inhibitors.

    abstract::Ependymoma is the third most common pediatric tumor with posterior fossa group A (PFA) being its most aggressive subtype. Ependymomas are generally refractory to chemotherapies and thus lack any effective treatment. Here, we report that elevated expression of CXorf67 (chromosome X open reading frame 67), which frequen...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccell.2020.10.009

    authors: Han J,Yu M,Bai Y,Yu J,Jin F,Li C,Zeng R,Peng J,Li A,Song X,Li H,Wu D,Li L

    更新日期:2020-12-14 00:00:00

  • Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model.

    abstract::Recent studies have identified genes and core pathways that are altered in human glioblastoma. However, the mechanisms by which alterations of these glioblastoma genes singly and cooperatively transform brain cells remain poorly understood. Further, the cell of origin of glioblastoma is largely elusive. By targeting a...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2009.04.001

    authors: Wang Y,Yang J,Zheng H,Tomasek GJ,Zhang P,McKeever PE,Lee EY,Zhu Y

    更新日期:2009-06-02 00:00:00

  • TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer.

    abstract::The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatoc...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccr.2010.03.021

    authors: Bettermann K,Vucur M,Haybaeck J,Koppe C,Janssen J,Heymann F,Weber A,Weiskirchen R,Liedtke C,Gassler N,Müller M,de Vos R,Wolf MJ,Boege Y,Seleznik GM,Zeller N,Erny D,Fuchs T,Zoller S,Cairo S,Buendia MA,Prinz M,A

    更新日期:2010-05-18 00:00:00

  • KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance.

    abstract::Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by...

    journal_title:Cancer cell

    pub_type: 杂志文章

    doi:10.1016/j.ccell.2018.10.014

    authors: Hinohara K,Wu HJ,Vigneau S,McDonald TO,Igarashi KJ,Yamamoto KN,Madsen T,Fassl A,Egri SB,Papanastasiou M,Ding L,Peluffo G,Cohen O,Kales SC,Lal-Nag M,Rai G,Maloney DJ,Jadhav A,Simeonov A,Wagle N,Brown M,Meissner A

    更新日期:2018-12-10 00:00:00