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contributes to cell survival during infection [ 209 ]. Mechanistically, the miRNAs
encoded by KSHV target and downregulate the HIF prolyl hydroxylase EGLN2 and
the heat shock protein HSPA9. The decrease of EGLN2 and HSPA9 stabilizes
HIF-1α and reduces mitochondrial numbers [ 210 ]. As a downstream effector of
HIF-1α, pyruvate kinase2 (PKM2) is upregulated upon KSHV infection [ 211 ]. The
M2 isoform of pyruvate kinase is characterized by its low affinity for its substrate
phosphoenol pyruvate, thereby serving as a rate-limiting checkpoint and facilitating
the accumulation of upstream intermediates during glycolysis for cancer anabolic
synthesis [ 209 ]. Under stress conditions such as nutrient deficiency, however,
KSHV miRNAs and vFLIP suppress both aerobic glycolysis and oxidative phos-
phorylation by downregulating the glucose transporters GLUT1 and GLUT3. The
reduced metabolic activities help KSHV adapt to stress and survive in the tumor
microenvironment [ 212 ]. In a condition opposite to that of excessive glucose provi-
sion, the augmented metabolism caused by high glucose induces hydrogen peroxide
production, which reduces the expression of silent information regulator 1 (SIRT1).
SIRT1 downregulation results in the epigenetic transactivation of KSHV lytic genes
and contributes to virus spread and reinfection, promoting KS development [ 213 ].
Glutaminolysis is also regulated by KSHV during infection [ 214 ]. KSHV induces
the Myc/Max and Mondo/Mix heterodimers to upregulate the glutamine transporter
SLC1A5, thereby promoting glutamine uptake. Glutamine is required for KSHV-
infected cells to supply intermediates for the tri-carboxylic acid (TCA) cycle and
macromolecule biosynthesis. SLC1A5 inhibition causes the death of KSHV- infected
but not that of mock-infected cells, indicating that the metabolic shift induced by
KSHV disturbs the physiological activity of infected cells [ 214 ]. With the excessive
production of intermediates, KSHV enhances biosynthetic pathways to generate
fatty acids and lipid droplet organelles [ 215 ], similar to other cancers. Although the
KSHV-induced altered metabolism is a relatively new field, growing evidence indi-
cates that KSHV-infected cells display the Warburg effect, which serves as a thera-
peutic target for treatment (Fig. 7.5).
7.5.5 KSHV-Induced Tumorigenesis
Cancer is characterized by sustained proliferation, resistance against cell death, eva-
sion of growth suppressors, angiogenesis, alterations in metabolism, evasion of
immune destruction, and activation of invasion and metastasis [ 208 ]. We discussed
above how KSHV induces angiogenesis, alters the cell metabolism, and regulates
the host immune system. As an established oncogenic virus, KSHV encodes pro-
teins that either activate oncogenes or inhibit tumor suppressors to escape cell death,
support proliferation, and help invasion. Here, we discuss further how KSHV trans-
forms cells by targeting multiple host factors.
Two key tumor suppressors, retinoblastoma protein (pRb) and p53 are inacti-vated by KSHV through multiple ways. pRb prevents excessive cell proliferation by
inhibiting cell cycle progression, and pRb inactivation retains host cells in the S
7 KSHV Epidemiology and Molecular Biology