Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive cancer with no currently available effective treatment. Understanding of the molecular mechanism of HCC development and progression is imperative for developing novel, effective, and targeted therapies for this lethal disease. In this article, we document that the cellular transcription factor Late SV40 Factor (LSF) plays an important role in HCC pathogenesis. LSF protein was significantly overexpressed in human HCC cells compared to normal hepatocytes. In 109 HCC patients, LSF protein was overexpressed in >90% cases, compared to normal liver, and LSF expression level showed significant correlation with the stages and grades of the disease. Forced overexpression of LSF in less aggressive HCC cells resulted in highly aggressive, angiogenic, and multiorgan metastatic tumors in nude mice. Conversely, inhibition of LSF significantly abrogated growth and metastasis of highly aggressive HCC cells in nude mice. Microarray studies revealed that as a transcription factor, LSF modulated specific genes regulating invasion, angiogenesis, chemoresistance, and senescence. The expression of osteopontin (OPN), a gene regulating every step in tumor progression and metastasis, was robustly up-regulated by LSF. It was documented that LSF transcriptionally up-regulates OPN, and loss-of-function studies demonstrated that OPN plays an important role in mediating the oncogenic functions of LSF. Together, these data establish a regulatory role of LSF in cancer, particularly HCC pathogenesis, and validate LSF as a viable target for therapeutic intervention.metastasis | osteopontin | transcription regulation H epatocellular carcinoma (HCC) is one of the five most common cancers worldwide (1). The incidence of HCC is increasing despite a decrease in overall incidence of all cancers (2, 3). In the United States, the estimated new cases of HCC for 2008 were 21,370, of which 18,410 were expected to die (2). The mortality rate of HCC parallels that of its incidence because HCC is a tumor with rapid growth and early vascular invasion that is resistant to conventional chemotherapy, and no systemic therapy is available for the advanced disease (4). As such, understanding the molecular mechanism of HCC development and progression is imperative to establish novel, effective, and targeted therapies for this highly aggressive cancer. Our recent studies reveal that astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human HCC patients, compared to normal liver, and AEG-1 plays a key role in regulating development and progression of HCC (5). The transcription factor Late SV40 Factor (LSF) was identified as a downstream gene of AEG-1, and we demonstrated that LSF mediates, in part, AEG-1-induced resistance to 5-fluorouracil (5-FU) in HCC cells (5, 6).LSF, also known as LBP-1c and TFCP2, regulates diverse cellular and viral promoters (7,8). A major cellular target of LSF is the thymidylate synthase (TS) gene, which encodes the ratelimiting enzyme in the production of dTTP, required for DNA ...

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

“…3A). Similar effects were observed in a hepatoblastoma cell line, Hep3B, in which LSF is also overexpressed (9), although requiring a longer time course of treatment (between 48 and 72 h; Fig. 3B).…”

“…We demonstrated that the transcription factor LSF can function as an oncogene for HCC (9), also recently confirmed by others (10). LSF, a member of a small family of transcription factors conserved throughout the animal kingdom (11), is ubiquitously expressed in mammalian tissues and cell lines (12).…”

“…We previously established that LSF was both sufficient and necessary for aggressive HCC tumor growth in mouse xenograft assays, and also that expression levels of LSF in human patient HCC samples correlated with increased stage and decreased differentiation state of disease (9). Taken together with the currently limited treatment options for HCC, the FQI compounds described here are promising candidates for pharmaceutical development for HCC treatment; they may also be effective agents in combating other cancers in which LSF serves as an oncogene.…”

“…In particular, QGY-7703 is an aggressive HCC cell line that expresses LSF at highly elevated levels. Expression of a dominant-negative mutant of LSF in QGY-7703 cells is sufficient to reduce growth of this cell line in vitro and to reduce tumor growth in xenograft models (9). In cell viability assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], both FQI1 and FQI2 decreased overall cellular proliferation of QGY-7703 cells (Fig.…”

“…Regulation of LSF activity normally occurs via posttranslational modifications, with LSF protein levels generally being low and constant. However, LSF protein levels are highly up-regulated in tumor cells, particularly in HCC cell lines and patient samples (9,17). These elevated LSF levels promote oncogenesis in the HCC cells.…”