BioProject

Transcription factors are important drivers of cancer but the development of therapeutics against these factors has had limited success. More...

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. Overall design: RNA-seq was performed on SALL4 knockdown and SALL4 overexpression cell line models to identify alterations in gene expression. Less...