Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Targeting the novel SALL4/CBL-B pathway by HDAC inhibitor MS-275 in lung cancer

ABSTRACT: The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling on SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Further studies revealed that SALL4 suppresses these pathways indirectly by repressing CBL-B. Connectivity Map analysis revealed HDAC inhibitor MS-275 as a potential drug in treating SALL4-expressing cancers and this was confirmed using 17 lung cancer cell lines. In summary, we report for the first time that MS-275 can target the novel SALL4/CBL-B pathway in lung cancer. This lays the foundation for future clinical studies to evaluate the therapeutic efficacy of MS-275 in SALL4-positive lung cancer patients. Cells from human lung carcinoma cell line H661 with wildtype scrambled controls or Sall4 knockdown were used for RNA extraction and hybridization on Affymetrix microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Henry Yang

PROVIDER: E-GEOD-68959 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Increasing studies suggest that SALL4 may play vital roles in leukemogenesis. We have used chromatin immunoprecipitation followed by microarray hybridization as a screening tool to determine potential genes that may account for the role SALL4 plays in leukemogenesis. Analysis of SALL4 binding sites reveals that genes involved in cell death, cancer, DNA replication/repair, and cell cycle were highly enriched (p<0.05). These genes include 38 important apoptosis-inducing genes (TNF, TP53, PTEN, CARD9, CARD11, CYCS, LTA) and apoptosis-inhibiting genes (Bmi-1, BCL2, XIAP, DAD1, TEGT). Real-time PCR has shown that expression levels of these genes changed significantly after SALL4 knockdown, which ubiquitously led to cell apoptosis. Flow cytometry revealed that reduction of SALL4 expression in NB4 and other leukemia cell lines dramatically increased caspase-3, Annexin V, and DNA fragmentation activity. Bromodeoxyuridine-incorporation assays showed decreased numbers of S phase cells and increased numbers of G1- and G2- phase cells indicating reduced DNA synthesis, consistent with results from cell proliferation assays. In addition, NB4 cells that express low levels of SALL4 have significantly decreased tumorigenecity in immunodeficient mice. Our studies provide a foundation in the development of leukemia stem cell-specific therapy by targeting SALL4. Keywords: ChIP-chip The global targets of SALL4 were determined using a NimbleGen promoter tiling array (2.7kb, information below) in the human cell line NB4. Because SALL4 is thought to play a significant role in leukemogenesis we focused primarily on genes involved in apoptosis and only used the ChIP-chip array as a screening tool to identify potential genes that may bind these genes. Upon identification and verification of apoptosis genes bound by SALL4 we utilized functional assays to determine the effect of SALL4 on these genes. In addition, gene expression profiling was used to determine pathways functionally altered by Sall4 reduction. Source: UCSC Build: HG18 Probe Length: 50-75mer Median Probe Spacing: 100bp Probes per Array: 385,000 Feature Size: 16Î¼m x 16Î¼m Array Dimensions: 17.4mm x 13mm Overall Slide Dimensions: 1" x 3" (25 x 75mm) Recommended Storage: Store arrays desiccated at room temperature. Promoter tiling from 2200bp upstream and 500bp downstream of the transcription start site for RefSeq genes.

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Targeting the novel SALL4/CBL-B pathway by HDAC inhibitor MS-275 in lung cancer

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