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Oncogenic targeting of BRM drives malignancy through C/EBP?-dependent induction of ?5 integrin.

ABSTRACT: Integrin expression and activity are altered in tumors, and aberrant integrin signaling promotes malignancy. However, how integrins become altered in tumors remains poorly understood. We discovered that oncogenic activation of MEK signaling induces cell growth and survival, and promotes the malignant phenotype of mammary epithelial cells (MECs) by increasing ?5 integrin expression. We determined that MEK activates c-Myc to reduce the transcription of the SWI/SNF chromatin remodeling enzyme Brahma (BRM). Our studies revealed that reduced BRM expression and/or activity drives the malignant behavior of MECs by epigenetically promoting C/EBP? expression to directly induce ?5 integrin transcription. Consistently, we could show that restoring BRM levels normalized the malignant behavior of transformed MECs in culture and in vivo by preventing C/EBP?-dependent ?5 integrin transcription. Our findings identify a novel mechanism whereby oncogenic signaling promotes malignant transformation by regulating transcription of a key chromatin remodeling molecule that regulates integrin-dependent stromal-epithelial interactions.

SUBMITTER: Damiano L

PROVIDER: S-EPMC3960370 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin.

Damiano L L Stewart K M KM Cohet N N Mouw J K JK Lakins J N JN Debnath J J Reisman D D Nickerson J A JA Imbalzano A N AN Weaver V M VM

Oncogene 20130617 19

Integrin expression and activity are altered in tumors, and aberrant integrin signaling promotes malignancy. However, how integrins become altered in tumors remains poorly understood. We discovered that oncogenic activation of MEK signaling induces cell growth and survival, and promotes the malignant phenotype of mammary epithelial cells (MECs) by increasing α5 integrin expression. We determined that MEK activates c-Myc to reduce the transcription of the SWI/SNF chromatin remodeling enzyme Brahm ...[more]

PMID: 23770848

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Project description:BackgroundOverexpression of CD98hc (SLC3A2) occurs in a variety of cancers and is suspected to contribute to tumor growth. CD98, a heterodimeric transmembrane protein, physically associates with certain integrin ? subunit cytoplasmic domains via its heavy chain, CD98hc. CD98hc regulates adhesion-induced intracellular signal transduction via integrins, thereby, affecting cell proliferation and clonal expansion. Disruption of CD98hc led to embryonic lethality in mice (E 3.5 and E 9.5) and CD98hc -/- embryonic stem cell transplantation failed to form teratomas, while CD98hc over-expression in somatic cells resulted in anchorage-independent growth. However, it is unclear whether interference with CD98hc expression tumor cell behavior.MethodsRenal cell cancer cell lines have been used to determine the effect of CD98hc expression on cancer cell behavior using cell adhesion, cell trans-migration and cell spreading assays. Flow cytometric analysis was performed to study the rate of apoptosis after detachment or serum starvation. shRNA-lentiviral constructs were used to stably knockdown or reconstitute full length or mutated CD98hc. The role of CD98 as a promotor of tumorigenesis was evaluated using an in in vivo tumor transplantation animal model. Immunohistochemical analysis was performed to analyze cell proliferation and CD98 expression in tumors.ResultsThis report shows that CD98hc silencing in clear cell renal cancer cells reverts certain characteristics of tumorigenesis, including cell spreading, migration, proliferation and survival in vitro, and tumor growth in vivo. Acquisition of tumorigenic characteristics in clear cell renal cancer cells occurred through the integrin binding domain of CD98hc. A CD98hc/integrin interaction was required for adhesion-induced sustained FAK phosphorylation and activation of the major downstream signaling pathways PI3k/Akt and MEK/ERK, while overexpression of a constitutive active form of FAK rescued the CD98hc deficiency.ConclusionsIn this study we demonstrate that loss of CD98hc blocks tumorigenic potential in renal cell cancer.

Dataset Information

Oncogenic targeting of BRM drives malignancy through C/EBP?-dependent induction of ?5 integrin.

Publications

Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin.

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