Submitted September 5, 2007
Accepted December 20, 2007
KSHV LANA inhibits TGF-
signaling through epigenetic silencing of the TGF- type II receptor
Daniel L. Di Bartolo, Mark Cannon, Yi-Fang Liu, Rolf Renne, Amy Chadburn, Chris Boshoff, and Ethel Cesarman*
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, United States
Cancer Research UK Viral Oncology Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom
Shands Cancer Center, University of Florida, Gainesville, FL, United States
* Corresponding author; email: ecesarm{at}med.cornell.edu.
Signaling through the TGF-
pathway results in growth inhibition and induction of apoptosis in various cell types. We show that this pathway is blocked in Kaposi's sarcoma herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) through downregulation of the TGF- type II receptor (TRII) by epigenetic mechanisms. Our data also suggests that KSHV infection may result in lower expression of TRII in Kaposi's sarcoma and multicentric Castleman's disease. KSHV-encoded LANA associates with the promoter of TRII and leads to its methylation and to the deacetylation of proximal histones. Reestablishment of signaling through this pathway reduces viability of these cells, inferring that KSHV-mediated blockage of TGF- signaling plays a role in the establishment and progression of KSHV-associated neoplasia. These data suggest a mechanism whereby KSHV evades the anti-proliferative effects of TGF- signaling by silencing TRII gene expression while allowing the immunosuppressive role of TGF- affect neighboring cells to evaade immune responses.
