Oncovirus KSHV represses tumor suppressor PDLIM2 to persistently activate NF-{kappa}B and STAT3 transcription factors for tumorigenesis and tumor maintenance [Molecular Bases of Disease]

February 13th, 2015 by Sun, F., Xiao, Y., Qu, Z.

KSHV is the most common cause of malignancies among AIDS patients. However, how KSHV induces tumorigenesis remains largely unknown. Here, we demonstrate that one important mechanism underlying the tumorigenesis of KSHV is through transcriptional repression of the tumor suppressor gene PDZ-LIM domain-containing protein 2 (PDLIM2). PDLIM2 expression is repressed in KSHV-transformed human umbilical vascular endothelial cells (HUVECs) as well as in KSHV-associated cancer cell lines and primary tumors. Importantly, PDLIM2 repression is essential for KSHV-induced persistent activation of nuclear factor kappaB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and subsequent tumorigenesis and tumor maintenance. Our mechanistic studies indicate that PDLIM2 repression by KSHV involves DNA methylation. Notably, the epigenetic repression of PDLIM2 can be reversed by 5-aza-2-deoxycytidine (5-aza-dC) and vitamin D to suppress KSHV-associated cancer cell growth. These studies not only improve our understanding of KSHV pathogenesis but also provide immediate therapeutic strategies for KSHV-mediated cancers, particularly those associated with AIDS.
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