TAF1D promotes proliferation by transcriptionally activating G2/M phase‐related genes in MYCN ‐amplified neuroblastoma

High‐risk neuroblastoma (HR‐NB) is an aggressive childhood cancer that responds poorly to currently available therapies and is associated with only about a 50% 5‐year survival rate. MYCN amplification is a critical driver of these aggressive tumors, but so far there have not been any approved treatments to effectively treat HR‐NB by targeting MYCN or its downstream effectors. Thus, the identification of novel molecular targets and therapeutic strategies to treat children diagnosed with HR‐NB represents an urgent unmet medical need. Here, we conducted a targeted siRNA screening and identified TATA box‐binding protein‐associated factor RNA polymerase I subunit D, TAF1D, as a critical regulator of the cell cycle and proliferation in HR‐NB cells. Analysis of three independent primary NB cohorts determined that high TAF1D expression correlated with MYCN‐amplified, high‐risk disease and poor clinical outcomes. TAF1D knockdown more robustly inhibited cell proliferation in MYCN‐amplified NB cells compared with MYCN‐non‐amplified NB cells, as well as suppressed colony formation and inhibited tumor growth in a xenograft mouse model of MYCN‐amplified NB. RNA‐seq analysis revealed that TAF1D knockdown downregulates the expression of genes associated with the G2/M transition, including the master cell‐cycle regulator, cell‐cycle‐dependent kinase 1 (CDK1), resulting in cell‐cycle arrest at G2/M. Our findings demonstrate that TAF1D is a key oncogenic regulator of MYCN‐amplified HR‐NB and suggest that therapeutic targeting of TAF1D may be a viable strategy to treat HR‐NB patients by blocking cell‐cycle progression and the proliferation of tumor cells.