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the promoters of p53 target genes [ 223 ]. Murine double minute 2 (MDM2), a p53

E3 ubiquitin ligase, targets p53 for ubiquitin-mediated degradation and is bound to

KSHV vIRF4 [ 224 ]. The interaction leads to reduced MDM2 auto- ubiquitination

and stabilizes MDM2. Stabilized MDM2 therefore facilitates proteasome- mediated

degradation of p53. In sum, KSHV regulates tumor suppressors such as p53 and

pRb at multiple phases.

In parallel with tumor suppressor inactivation, KSHV promotes tumorigenesis

by activating oncogenes and related signaling pathways. Two well-known KSHV-

encoded oncogenes are LANA and vGPCR. The regulation of p53 by LANA was

discussed extensively; however, LANA itself can activate a number of oncogenes.

Notch signaling is highly correlated with oncogenesis, and LANA stabilizes

intracellular- activated Notch (ICN) by inhibiting the E3 ligase Sel10 [ 225 ]. Another

critical signaling pathway is mediated by the TGF-β superfamily, which includes

TGF-β and BMP. TGF-β inhibits tumorigenesis at an early stage, and KSHV devel-

ops multiple mechanisms to repress it. KSHV-encoded miR-K12-11, a homolog of

the oncogenic host miR-155, downregulates Smad5 and attenuates TGF-β signaling

[ 129 ]. On the other hand, LANA silences the TGF-β type II receptor (TbetaRII) by

modulating the modification of the TbetaRII promoter [ 226 ]. BMP, however, pro-

motes malignancy through its downstream effector inhibitor of DNA-binding (Id)

proteins. LANA binds to and sustains BMP-activated p-Smad1  in the nucleus,

which leads to aberrant Ids expression and tumorigenesis [ 227 ]. vGPCR is involved

in KS progression by regulating multiple cellular pathways including MAPK/ERK,

PI3K/Src, and the TSC2/mTOR axis [ 228 , 229 ], which are well-known oncogenic

signaling pathways. In addition, vGPCR collaborates with HIV-1 Tat to accelerate

KS progression [ 230 ], confirming that coinfection with HIV is critical for KSHV-

induced pathogenesis.

Collectively, KSHV modulates multiple aspects of cellular activity, which

together contribute to KSHV-induced tumorigenesis.

7.5.6 Treatment of KSHV-Related Diseases

Combination antiretroviral therapy (cART) is the most common treatment for HIV-

related KS. The incidence of KS has decreased significantly where cART is avail-

able. However, cART acts by controlling HIV, as HIV creates a milieu permissive

for KSHV to promote KS formation. Regarding KS itself, there is a lack of effective

targeted therapeutics. Because it is a highly vascularized tumor, therapeutic

approaches that inhibit KS angiogenesis are promising. VEGF-neutralizing anti-

bodies and tyrosine kinase inhibitors show efficacy in KS [ 230 – 232 ]. The cellular

signaling pathways hijacked by KSHV to promote tumorigenesis, such as PI3K/

Akt/mTOR and Notch, were discussed extensively. Consistent with this, rapamycin

(mTOR inhibitor) displays clinical activity against KS [ 232 – 234 ]. Despite the fact

that KSHV has been studied for more than two decades, further investigation of its

role in disease progression is challenging because of a lack of in  vivo animal

7 KSHV Epidemiology and Molecular Biology