Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with
Kaposi's sarcoma (KS), a
malignancy commonly found in
AIDS patients. Despite intensive studies in the last two decades, the mechanism of KSHV-induced cellular transformation and
tumorigenesis remains unclear. In this study, we found that the expression of
SIRT1, a metabolic sensor, was upregulated in a variety of KSHV-infected cells. In a model of KSHV-induced cellular transformation,
SIRT1 knockdown with shRNAs or knockout by CRISPR/Cas9 gene editing dramatically suppressed cell proliferation and colony formation in soft
agar of KSHV-transformed cells by inducing cell cycle arrest and contact inhibition.
SIRT1 knockdown or knockout induced the expression of
cyclin-dependent kinase inhibitor 1B (p27Kip1). Consequently, p27 knockdown rescued the inhibitory effect of
SIRT1 knockdown or knockout on cell proliferation and colony formation. Furthermore, treatment of KSHV-transformed cells with a
SIRT1 inhibitor,
nicotinamide (NAM), had the same effect as
SIRT1 knockdown and knockout. NAM significantly inhibited cell proliferation in culture and colony formation in soft
agar, and induced cell cycle arrest. Significantly, NAM inhibited the progression of
tumors and extended the survival of mice in a KSHV-induced
tumor model. Collectively, these results demonstrate that
SIRT1 suppression of p27 is required for KSHV-induced
tumorigenesis and identify a potential therapeutic target for KS.