Am J Cancer Res 2012;2(3):269-285
Review Article
The transcription factor LSF: a novel oncogene for hepatocellular carcinoma
Prasanna K Santhekadur, Devaraja Rajasekaran, Ayesha Siddiq, Rachel Gredler, Dong Chen, Scott E Schaus, Ulla Hansen,
Paul B Fisher, Devanand Sarkar
Department of Human and Molecular Genetics, Department of Pathology, 5VCU Institute of Molecular Medicine and 6VCU
Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA; Department of
Chemistry, Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) and Department of
Biology, Boston University, Boston, MA 02215, USA
Received March 2, 2012; accepted April 5, 2012; Epub April 21, 2012; Published May 15, 2012
Abstract: The transcription factor LSF (Late SV40 Factor), also known as TFCP2, belongs to the LSF/CP2 family related to
Grainyhead family of proteins and is involved in many biological events, including regulation of cellular and viral promoters, cell
cycle, DNA synthesis, cell survival and Alzheimer’s disease. Our, recent studies establish an oncogenic role of LSF in
Hepatocellular carcinoma (HCC). LSF overexpression is detected in human HCC cell lines and in more than 90% cases of
human HCC patients, compared to normal hepatocytes and liver, and its 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 multi-organ 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. LSF transcriptionally regulates
thymidylate synthase (TS) gene, thus contributing to cell cycle regulation and chemoresistance. Our studies identify a network of
proteins, including osteopontin (OPN), Matrix metalloproteinase-9 (MMP-9), c-Met and complement factor H (CFH), that are
directly regulated by LSF and play important role in LSF-induced hepatocarcinogenesis. A high throughput screening identified
small molecule inhibitors of LSF DNA binding and the prototype of these molecules, Factor Quinolinone inhibitor 1 (FQI1),
profoundly inhibited cell viability and induced apoptosis in human HCC cells without exerting harmful effects to normal immortal
human hepatocytes and primary mouse hepatocytes. In nude mice xenograft studies, FQI1 markedly inhibited growth of human
HCC xenografts as well as angiogenesis without exerting any toxicity. These studies establish a key role of LSF in
hepatocarcinogenesis and usher in a novel therapeutic avenue for HCC, an invariably fatal disease. (AJCR00000110).
Keywords: Late SV40 Factor (LSF), hepatocellular carcinoma (HCC), osteopontin (OPN), matrix metalloproteinase-9 (MMP-9), c-
Met, thymidylate synthase (TS), angiogenesis, metastasis, cell cycle regulation, small molecule inhibitors, FQI1
Address all correspondence to:
Dr. Devanand Sarkar
1220 East Broad St, Room 7044, PO Box 980035
Richmond, VA 23298, USA.
Tel: 804-827-2339; Fax: 804-628-1176
E-mail: dsarkar@vcu.edu
Review Article
The transcription factor LSF: a novel oncogene for hepatocellular carcinoma
Prasanna K Santhekadur, Devaraja Rajasekaran, Ayesha Siddiq, Rachel Gredler, Dong Chen, Scott E Schaus, Ulla Hansen,
Paul B Fisher, Devanand Sarkar
Department of Human and Molecular Genetics, Department of Pathology, 5VCU Institute of Molecular Medicine and 6VCU
Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA; Department of
Chemistry, Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) and Department of
Biology, Boston University, Boston, MA 02215, USA
Received March 2, 2012; accepted April 5, 2012; Epub April 21, 2012; Published May 15, 2012
Abstract: The transcription factor LSF (Late SV40 Factor), also known as TFCP2, belongs to the LSF/CP2 family related to
Grainyhead family of proteins and is involved in many biological events, including regulation of cellular and viral promoters, cell
cycle, DNA synthesis, cell survival and Alzheimer’s disease. Our, recent studies establish an oncogenic role of LSF in
Hepatocellular carcinoma (HCC). LSF overexpression is detected in human HCC cell lines and in more than 90% cases of
human HCC patients, compared to normal hepatocytes and liver, and its 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 multi-organ 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. LSF transcriptionally regulates
thymidylate synthase (TS) gene, thus contributing to cell cycle regulation and chemoresistance. Our studies identify a network of
proteins, including osteopontin (OPN), Matrix metalloproteinase-9 (MMP-9), c-Met and complement factor H (CFH), that are
directly regulated by LSF and play important role in LSF-induced hepatocarcinogenesis. A high throughput screening identified
small molecule inhibitors of LSF DNA binding and the prototype of these molecules, Factor Quinolinone inhibitor 1 (FQI1),
profoundly inhibited cell viability and induced apoptosis in human HCC cells without exerting harmful effects to normal immortal
human hepatocytes and primary mouse hepatocytes. In nude mice xenograft studies, FQI1 markedly inhibited growth of human
HCC xenografts as well as angiogenesis without exerting any toxicity. These studies establish a key role of LSF in
hepatocarcinogenesis and usher in a novel therapeutic avenue for HCC, an invariably fatal disease. (AJCR00000110).
Keywords: Late SV40 Factor (LSF), hepatocellular carcinoma (HCC), osteopontin (OPN), matrix metalloproteinase-9 (MMP-9), c-
Met, thymidylate synthase (TS), angiogenesis, metastasis, cell cycle regulation, small molecule inhibitors, FQI1
Address all correspondence to:
Dr. Devanand Sarkar
1220 East Broad St, Room 7044, PO Box 980035
Richmond, VA 23298, USA.
Tel: 804-827-2339; Fax: 804-628-1176
E-mail: dsarkar@vcu.edu
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American Journal of Cancer Research
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