Targeted repression of UBTF inhibits growth and metastatic phenotypes of pancreatic cancer via inhibition of ribosome biogenesis

Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the United States due to lack of molecular understanding, diagnostic methods and effective therapeutic options. Emerging evidence suggests that cancer cells alter ribosome biogenesis machinery at genetic and epigenetic levels to meet high demand of protein synthesis. This study reveals a UBTF mediated novel ribosome biogenesis-associated molecular mechanism that might be crucial for pancreatic cancer progression. Our study suggests upregulation of UBTF, an upstream binding transcription factor (member of the HMG-box DNA-binding protein family) in pancreatic tumors. Its stable shRNA mediated knockdown in human PanCa cells (HPAF-II and MIA PaCa-2) showed remarkable decrease in tumorigenic and metastatic phenotypes of these cells in different functional assays (cell proliferations, colony formation, migration, invasion assays) along with altered expression of E-Cadherin (increase) and N-Cadherin (decrease). Additionally, ChIP assay showed that UBTF-knockdown decreased the occupancy of key components of RNA Polymerase I complex such as RPA194, RPA135, TAF1C and Rrn3 on rDNA which leads to the reduced transcription of rDNA products such as 5' ETS (a marker of pre-rRNA synthesis) and 18S rRNA in these cells. The UBTF repression also effectively inhibited tumor growth in ectopic xenograft mouse model and the growth inhibition was correlated with decreased expression of proliferative (PCNA and Ki67), and ribosome biogenesis (UBTF, RPA194) markers as compared to respective controls tumors. These findings suggest a critical role of UBTF in ribosome biogenesis in pancreatic cancer and that its strategic inhibition could be helpful for developing new therapeutic strategies for pancreatic cancer. In conclusion, this study elucidates a new molecular mechanism that can serve as a potential target for pancreatic cancer treatment.