Oncotarget

Research Papers:

SIRT1-mediated downregulation of p27Kip1 is essential for overcoming contact inhibition of Kaposi's sarcoma-associated herpesvirus transformed cells

Meilan He, Hongfeng Yuan, Brandon Tan, Rosemary Bai, Heon Seok Kim, Sangsu Bae, Lu Che, Jin-Soo Kim and Shou-Jiang Gao _

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Oncotarget. 2016; 7:75698-75711. https://doi.org/10.18632/oncotarget.12359

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Abstract

Meilan He1,*, Hongfeng Yuan1,*, Brandon Tan1, Rosemary Bai1, Heon Seok Kim2,3, Sangsu Bae2,4, Lu Che1, Jin-Soo Kim2,3, Shou-Jiang Gao1

1Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California Los Angeles, Los Angeles, CA, USA

2Center for Genome Engineering, Institute for Basic Science, Seoul, South Korea

3Department of Chemistry, Seoul National University, Seoul, South Korea

4Present address: Department of Chemistry, Hanyang University, Seoul, South Korea

*These authors have contributed equally to this work

Correspondence to:

Shou-Jiang Gao, email: shoujiag@usc.edu

Keywords: SIRT1, p27Kip1, Kaposi’s sarcoma-associated herpesvirus, cellular transformation

Received: June 20, 2016    Accepted: September 21, 2016    Published: September 30, 2016

ABSTRACT

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.


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