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A high-throughput screen reveals SALL4-induced oxidative phosphorylation vulnerabilities in cancer

ABSTRACT: Transcription factors are important drivers of cancer but the development of therapeutics against these factors has had limited success. We developed a stringent high-throughput chemical genetic screening platform to identify compounds that target oncogene SALL4 dependency in liver cancer. The platform comprises SALL4 low- and high-expressing endogenous cell lines, and engineered SALL4-low isogenic lines overexpressing SALL4. We identified 4 oxidative phosphorylation (OXPHOS) inhibitors, from screening 21,575 natural product extracts, that selectively reduce SALL4-dependent cell viability. ATP synthase inhibitor Oligomycin suppresses SALL4-expressing cancer in culture and in vivo. When aberrantly overexpressed in cancer, SALL4 binds ~50% of OXPHOS and other mitochondrial genes, upregulating their expression. SALL4 upregulation also functionally increases OXPHOS. Our endogenous/isogenic transcription factor-screening platform reveals a therapeutically actionable OXPHOS vulnerability in SALL4-expressing cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114808 | GEO | 2019/10/28

REPOSITORIES: GEO

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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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A high-throughput screen reveals SALL4-induced oxidative phosphorylation vulnerabilities in cancer

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