Our major research interests concern how mammalian cell growth and cell cycle are regulated, and how misregulation, particularly of transcription factors, drives oncogenesis. We focus on the cell cycle-regulated transcription factor LSF, recently shown to be an oncogene for liver cancer. Studies range from critical genes targeted by LSF to control cell cycle progression, to signal transduction pathways that modify LSF to alter its activity, to biological consequences of inhibiting or inducing LSF activity. We also use bioinformatics tools to understand the transcriptional regulatory networks driving proliferation.
LSF controls several stages of cell cycle progression. Although its protein levels stay constant in normal cells, its activity is tightly regulated during cell growth stimulation and cell cycle progression. In particular, we have shown that during the critical transition through G1 phase to DNA replication, LSF activity is regulated by phosphorylation at a number of sites, in response to multiple signaling pathways. In this process, the phosphorylation-dependent prolyl isomerase Pin1 binds LSF and alters its activity. At the G1/S transition, LSF contributes to the activation of a number of genes required for DNA replication.
Inhibition of LSF causes apoptosis. Under some circumstances, this occurs through inhibition of thymidylate synthase, an essential enzyme for nucleotide biosynthesis and DNA replication that many cancer chemotherapeutic drugs specifically inhibit. A highly specific small molecule inhibitor of LSF activity, which we recently identified, is antiproliferative in many cell types, and drives apoptosis of highly aggressive hepatocellular carcinoma cells. In mouse tumor models, these inhibitors dramatically reduce tumor growth, with no to minimal toxicity to other tissues. Our current interests include developing this, and other LSF small molecule inhibitors, for chemotherapeutics of cancers overexpressing LSF, as is the case for primary liver cancer.
- Willoughby JLS, George K, Roberto MP, Chin HG, Stoiber P, Shin H, Pedamallu CS, Schaus SE, Fitzgerald K, Shah J, Hansen U. (2020) Targeting the oncogene LSF with either the small molecule inhibitor FQI1 or siRNA causes mitotic delays with unaligned chromosomes, resulting in cell death or senescence. BMC Cancer, 20: 552.
- Chin HG, Estève PO, Ruse C, Lee J, Schaus SE, Pradhan S, Hansen U. (2020) The microtubule-associated histone methyltransferase SET8, facilitated by transcription factor LSF, methylates α-tubulin. Journal of Biological Chemistry, 295: 4748-4759.
- Chin HG, Ponnaluri C, Zhang G, Estève P-O, Schaus SE, Hansen U, Pradhan S (2016) Transcription factor LSF-DNMT1 complex dissociation by FQI1 leads to aberrant DNA methylation and gene expression. Oncotarget 7: 83627-83640.
- Rajasekaran D, Siddiq A, Willoughby JLS, Biagi JM, Christadore LM, Yunes SA, Gredler R, Jariwala N, Robertson CL, Akiel MA, Shen X-N, Subler MA, Windle JJ, Schaus SE, Fisher PB, Hansen U, Sarkar D (2015) Small molecule inhibitors Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model. Oncotarget 6: 26266-26277.
- Grant TJ, Bishop JA, Christadore LM, Barot G, Chin HG, Woodson S, Kavouris J, Siddiq A, Gredler R, Shen XN, Sherman J, Meehan T, Fitzgerald K, Pradhan S, Briggs LA, Andrews WH, Sarkar D, Schaus SE, Hansen U (2012) Antiproliferative small molecule inhibitors of the transcription factor LSF reveal oncogene addiction in hepatocellular carcinoma. Proceedings of the National Academy of Sciences, U.S.A., 109: 4503-4508.
- Schneider S, Smith T, Hansen U (2011) SCOREM: Statistical consolidation of redundant expression measures. Nucleic Acids Research, doi: 10.1093/nar/gkr1270.
- Saxena UH, Owens L, Graham JR, Cooper GM, Hansen U (2010) Prolyl isomerase Pin1 regulates transcription factor LSF (TFCP2) by facilitating dephosphorylation at two serine-proline motifs. J. Biol. Chem. 285: 31139-31147.
- Hansen U, Owens L, Saxena UH (2009). Transcription factors LSF and E2Fs: Tandem cyclists driving G0 to S? Cell Cycle, 8: 2146-2151.
- Licht JD, Grossel MJ, Figge J, Hansen U (1990) Drosophila Krüppel protein is a transcriptional repressor. Nature 346: 76-79.
- BI 753 Advanced Molecular Biology
- BI 203 Cell Biology