Oncogenic herpesvirus KSHV Hijacks BMP-Smad1-Id signaling to promote tumorigenesis.

Deguang Liang,Hao Hu,Shou-Jiang Gao,Yuhan Wang,Li He,Xing Wang,Yuan Gao,Jiazhen Dong,Shasha Li,Ke Lan,Zhiheng He,Paul M Lieberman

doi:10.1371/journal.ppat.1004253

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), a malignancy commonly found in AIDS patients. Whether KS is a true neoplasm or hyperplasia has been a subject of intensive debate until recently when KSHV is unequivocally shown to efficiently infect, immortalize and transform rat primary mesenchymal precursor cells (MM). Moreover, KSHV-transformed MM cells (KMM) efficiently induce tumors with hallmark features of KS when inoculated into nude mice. Here, we showed Smad1 as a novel binding protein of KSHV latency-associated nuclear antigen (LANA). LANA interacted with and sustained BMP-activated p-Smad1 in the nucleus and enhanced its loading on the Id promoters. As a result, Ids were significantly up-regulated in KMM cells and abundantly expressed in human KS lesions. Strikingly, genetic and chemical inhibition of the BMP-Smad1-Id pathway blocked the oncogenic phenotype of KSHV-transformed cells in vitro and in vivo. These findings illustrate a novel mechanism by which a tumor virus hijacks and converts a developmental pathway into an indispensable oncogenic pathway for tumorigenesis. Importantly, our results demonstrate the efficacy of targeting the BMP-Smad1-Id pathway for inhibiting the growth of KSHV-induced tumors, and therefore identify the BMP pathway as a promising therapeutic target for KS.

Highlights

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS), which is the most common malignancy in AIDS patients [1]
KSHV exerts multiple mechanisms to promote cell survival by repressing transforming growth factor b (TGF-b) signaling, little is known whether KSHV manipulates Bone morphogenetic proteins (BMPs) signaling and contributes to the pathogenesis of KSHV-induced malignancies
We showed that BMP signaling inhibitors dramatically hampered the tumorigenicity of KSHV-transformed MM cells (KMM) cells in vitro and in vivo

Summary

Introduction

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS), which is the most common malignancy in AIDS patients [1]. The KSHV-infected proliferating spindle cells are the driving force of KS [2]. KSHV mainly displays latency in spindle cells. Viral latent genes were reported to promote cell proliferation and inhibit apoptosis through various mechanisms. Latency-associated nuclear antigen (LANA), a multifunctional major viral latent protein, is responsible for maintaining viral episome, inhibiting viral reactivation, and promoting cell proliferation by targeting p53, pRb and GSK-3b, etc (reviewed in [3,4]). We have shown that LANA contributes to cell proliferation by promoting intracellular Notch (ICN) accumulation through inhibition of Sel10-mediated ICN degradation [5,6]

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