HPP1-mediated tumor suppression requires activation of STAT1 pathways.
HPP1 is a recently discovered gene that is epigenetically silenced in a number of tumor types, suggesting a potential role as a tumor suppressor. However, whether HPP1 has tumor suppressor activity is not clearly known. We have sought to investigate the effects of HPP1 on tumor growth and survival and to identify signaling pathways that mediate HPP1's mechanism of action. Forced expression of HPP1 into HCT116 colon cancer cell lines blocked the ability of HCT116 tumors to grown in vivo in nude mice. In cell culture, ectopic expression of HPP1 induces apoptosis and potently inhibits soft agar colony formation. HPP1 overexpression was also associated with a moderate reduction in in vitro proliferation characterized by an accumulation of cells in the G0/G1 phase of the cell cycle. Microarray analysis revealed that ectopic expression of HPP1 resulted in a dramatic upregulation of STAT1 as well as a large number of associated interferon-inducible genes. RNA interference-mediated abrogation of STAT1 reversed HPP1's antiproliferative effects. We conclude that HPP1 demonstrates tumor suppressive and pro-apoptotic activity, both in vitro and in vivo. Coupled with its inactivation in a number of tumor types, our data provides evidence to support the role of HPP1 as a tumor suppressor gene. Moreover, activation of the STAT1 pathway likely represents the principal mediator of HPP1's tumor suppressive properties.
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Abul
A
Elahi
Li
L
Zhang
Timothy J
TJ
Yeatman
Sigal
S
Gery
Said
S
Sebti
David
D
Shibata
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation
D008565:Membrane Proteins; D009363:Neoplasm Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C423567:TMEFF2 protein, human; D025521:Tumor Suppressor Proteins