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Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-?B.

ABSTRACT: Anoikis-resistance of tumor cells is critical for anchorage-independent growth and metastasis. The inflammatory-response transcription factor NF-?B contributes to anoikis-resistance and tumor progression through mechanisms that are understood incompletely. Deleted in breast cancer-1 (DBC1) protein (KIAA1967) is over-expressed in several tumor types, and correlates with a poorer prognosis in some cases. We report here that DBC1 suppressed anoikis in normal epithelial and breast cancer cell lines. DBC1 interacted with IKK-?, stimulating its kinase activity, promoting NF-?B transcriptional activity through the phosphorylation of relA serine-536 and enhancing the expression of the NF-?B target genes, c-FLIP and bcl-xl. Our results indicate that DBC1 is an important co-factor for the control of the IKK-?-NF-?B signaling pathway that regulates anoikis.

SUBMITTER: Park SH

PROVIDER: S-EPMC3691317 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-κB.

Park Sun Hee SH Riley Philip P Frisch Steven M SM

Apoptosis : an international journal on programmed cell death 20130801 8

Anoikis-resistance of tumor cells is critical for anchorage-independent growth and metastasis. The inflammatory-response transcription factor NF-κB contributes to anoikis-resistance and tumor progression through mechanisms that are understood incompletely. Deleted in breast cancer-1 (DBC1) protein (KIAA1967) is over-expressed in several tumor types, and correlates with a poorer prognosis in some cases. We report here that DBC1 suppressed anoikis in normal epithelial and breast cancer cell lines. ...[more]

PMID: 23588592

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Project description:Deleted in breast cancer 1 (DBC1) has emerged as an important regulator of multiple cellular processes, ranging from gene expression to cell cycle progression. DBC1 has been linked to tumorigenesis both as an inhibitor of histone deacetylases, HDAC3 and sirtuin 1, and as a transcriptional cofactor for nuclear hormone receptors. However, despite mounting interest in DBC1, relatively little is known about the range of its interacting partners and the scope of its functions. Here, we carried out a functional proteomics-based investigation of DBC1 interactions in two relevant cell types, T cells and kidney cells. Microscopy, molecular biology, biochemistry, and mass spectrometry studies allowed us to assess DBC1 mRNA and protein levels, localization, phosphorylation status, and protein interaction networks. The comparison of DBC1 interactions in these cell types revealed conserved regulatory roles for DBC1 in gene expression, chromatin organization and modification, and cell cycle progression. Interestingly, we observe previously unrecognized DBC1 interactions with proteins encoded by cancer-associated genes. Among these interactions are five components of the SWI/SNF complex, the most frequently mutated chromatin remodeling complex in human cancers. Additionally, we identified a DBC1 interaction with TBL1XR1, a component of the NCoR complex, which we validated by reciprocal isolation. Strikingly, we discovered that DBC1 associates with proteins that regulate the circadian cycle, including DDX5, DHX9, and SFPQ. We validated this interaction by colocalization and reciprocal isolation. Functional assessment of this association demonstrated that DBC1 protein levels are important for regulating CLOCK and BMAL1 protein oscillations in synchronized T cells. Our results suggest that DBC1 is integral to the maintenance of the circadian molecular clock. Furthermore, the identified interactions provide a valuable resource for the exploration of pathways involved in DBC1-associated tumorigenesis.

Dataset Information

Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-?B.

Publications

Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-κB.

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