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PMID:18850004

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Citation

Mottet, D, Pirotte, S, Lamour, V, Hagedorn, M, Javerzat, S, Bikfalvi, A, Bellahcène, A, Verdin, E and Castronovo, V (2009) HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism. Oncogene 28:243-56

Abstract

Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptional reactivation of the p21(WAF1/Cip1)gene. The HDACs that regulate p21(WAF1/Cip1) are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21(WAF1/Cip1) through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1). Induction of p21(WAF1/Cip1) mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs.

Links

PubMed Online version:10.1038/onc.2008.371

Keywords

Acetylation; Animals; Binding Sites; Bone Neoplasms/pathology; Brain Neoplasms/drug therapy; Brain Neoplasms/pathology; Cell Line, Tumor/metabolism; Chick Embryo; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis; Cyclin-Dependent Kinase Inhibitor p21/genetics; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glioblastoma/drug therapy; Glioblastoma/pathology; HeLa Cells/drug effects; HeLa Cells/metabolism; Histone Deacetylase Inhibitors; Histone Deacetylases/physiology; Histones/metabolism; Humans; Neoplasm Proteins/antagonists & inhibitors; Neoplasm Proteins/physiology; Osteosarcoma/pathology; Protein Processing, Post-Translational; RNA, Messenger/biosynthesis; RNA, Neoplasm/biosynthesis; Repressor Proteins/antagonists & inhibitors; Repressor Proteins/physiology; Sp1 Transcription Factor/physiology; Tumor Suppressor Protein p53/antagonists & inhibitors; Tumor Suppressor Protein p53/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SP1

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SP1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:SP1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P56524

F

Seeded From UniProt

complete

HUMAN:HDAC4

contributes_to

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HDAC4

involved_in

GO:0006338: chromatin remodeling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC4

involved_in

GO:0043433: negative regulation of DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC4

involved_in

GO:0016575: histone deacetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC4

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC4

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC4

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08047

F

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08047

F

Seeded From UniProt

complete

HUMAN:CDN1A

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08047

F

Seeded From UniProt

complete

HUMAN:HDAC1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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