TAF1D Functions as a Novel Biomarker in Osteosarcoma.

Background: The most frequent primary bone cancer in teenagers, osteosarcoma (OS), is particularly aggressive with a high mortality rate. Methods: By combining public databases, OS and non-cancer samples were obtained. The Wilcoxon test and standardized mean difference (SMD) were utilized to evaluate the mRNA expression level of TATA-box binding protein associated factor, RNA polymerase 1 subunit D (TAF1D). The potential of TAF1D to discriminate OS samples from non-cancer samples was revealed by summary receiver operating characteristic curve (sROC). To investigate the prognostic significance, Kaplan‒Meier curve and univariate Cox analysis were performed. Immunohistochemistry (IHC) was used to determine the TAF1D protein expression level. ESTIMATE algorithm and TIMER2.0 database were used to reveal the association between TAF1D expression and the immune microenvironment. Enrichment analysis and potential drug prediction were performed to clarify the underlying molecular mechanisms and possible therapeutic directions of TAF1D. Ultimately, the transcription factors (TFs) and the TAF1D binding site were predicted based on the Cistrome and JASPAR databases. Results: TAF1D was upregulated in OS at the mRNA and protein levels and possessed robust discriminatory power. TAF1D upregulation was suggestive of worse prognosis and enhancement of tumor purity in OS patients. The cell cycle was the most significantly enriched pathway, and NU.1025 was considered to be the potential target agent. Finally, MYC was identified as a TF that regulates the expression of TAF1D. Conclusions: Altogether, TAF1D has the potential to serve as a biological marker and therapeutic target in OS, which could offer new perspectives for OS treatment.

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.