Oncogene-induced senescence (OIS) represents an important barrier to tumor initiation, sensing oncogenic stress and enforcing permanent cell cycle arrest. The OIS program is rapid and dynamic. Oncogene activation causes transient hyper-proliferation that results in genotoxic stress and activation of DNA damage responses (DDRs) that initiate cell cycle exit. Autophagy is an important effector mechanism of OIS; during the transition to the senescent phenotype, increases in autophagic flux coincide with active translation, causing dramatic increases in cell size and production of secretory proteins that reinforce senescence (known as the senescence-associated secretory phenotype—SASP). Several autophagy genes have been assigned roles as tumor suppressors, and experimental disruption of autophagy promotes senescence bypass. The accumulating evidence suggests that autophagy can contribute to tumor suppression by enforcing OIS.
Approximately 15% of all human cancers share an underlying infectious etiology. Kaposi’s sarcoma-associated herpesvirus (KSHV, a.k.a. human herpesvirus-8) is the infectious cause of a dermal tumor known as Kaposi’s sarcoma (KS). Like all herpesviruses, KSHV can establish a reversible form of quiescent infection known as latency. During latency, the KSHV genome is physically tethered to host chromatin and viral gene expression is limited to a subset of gene products that perform important housekeeping functions. KS tumors are replete with latently infected endothelial cells (ECs) that proliferate abnormally, so KSHV latent gene products are also presumed to play important roles in disabling host antiproliferative defenses.
Our recent study revealed that cells latently infected with KSHV display clear indications of oncogenic stress and activated DDRs, but are refractory to senescence, suggesting active viral evasion of the OIS program. Therefore, we hypothesized that latent gene products undermine OIS and allow the ongoing proliferation of KSHV-infected cells despite the accrual of DNA damage. We identified two such gene products, viral-cyclin (v-cyclin) and viral-FLICE-inhibitory protein (v-CFLAR/v-FLIP), that coordinate an attack on host cell antiproliferative defenses. A striking feature of the KSHV genome is the presence of more than a dozen pirated human genes, the legacy of millennia of co-evolution between this lineage of viruses and our primate ancestors. Even more fascinating is the fact that two of these pirated genes, v-cyclin and v-CFLAR/v-FLIP, are co-expressed from the same spliced latent transcript, an arrangement that suggests functional interdependence (). The complementary roles that v-cyclin and v-CFLAR/v-FLIP play in controlling OIS provides a solid rationale for their genetic linkage.
Figure 1. v-CFLAR/v-FLIP subversion of autophagy impairs v-Cyclin OIS. (A) Schematic of the KSHV latent transcription unit encoding LANA, v-cyclin and v-CFLAR/v-FLIP. v-CFLAR/v-FLIP translation initiates from an internal ribosomal entry site (IRES). (more ...)