KSHV LANA's expanding bag of tricks

In this issue of Blood, Di Bartolo and colleagues report that KSHV targets the TGF-β signaling pathway in latently infected tumor cells.

Kaposi sarcoma–associated herpesvirus (KSHV) infection¹  has a causative role in Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). In tumor cells, the virus predominantly exists in a latent state in which the viral genome is maintained as a multicopy plasmid (or episome). Latently infected cells express only several of the virus's approximately 100 genes. These few genes exert critical effects on the host cell that deregulate its growth.

The KSHV latency-associated nuclear antigen (LANA)²  is the predominant viral antigen expressed during latent infection. Several key functions have been attributed to LANA. A critical obstacle that an episomal virus (which is not integrated into cell chromosomes) must overcome is to maintain its genetic material in proliferating cells. LANA fills this void by ensuring that the KSHV genome is replicated during each cell cycle. LANA then tethers newly replicated KSHV genomes to mitotic chromosomes, thereby using a “piggyback” mechanism to ensure KSHV DNA distribution to daughter-cell nuclei.

In addition to its role in genome maintenance, LANA also exerts effects on transcription and cell growth. Tumor viruses such as KSHV often directly deregulate critical cell-growth pathways, rather than relying on the accrual of mutations within the pathways, as occurs in many other human malignancies. While the precise molecular mechanisms whereby KSHV exerts its tumorigenic effects remain to be elucidated, it is becoming more and more evident that LANA plays a key role in this process. LANA has been shown to have effects on the tumor suppressor functions of Rb and p53. In addition, LANA activates c-Myc, a critical regulator of cell growth, and also the Wnt signaling pathway by inappropriately increasing β-catenin levels.

Disruption of TGF-β signaling is common to many human cancers, a strong indication that dysregulation of this pathway is a key step for malignant transformation.³  In their article, Di Bartolo and colleagues observe that PEL cell lines are nonresponsive to the growth-inhibitory and apoptotic effects of TGF-β treatment, due to the absence of TGF type II receptor (TβRII) expression. As might be expected in a KSHV-induced malignancy, this is not due to mutation in the TβRII gene, but instead is due to inappropriate methylation of the TβRII promoter at 2 key transcription-factor binding sites, as well as histone deacetylation at the promoter. The authors were able to recapitulate these events in an uninfected B-cell lymphoma cell line, and show that ectopic expression of LANA alone was sufficient to increase methylation and decrease histone acetylation at the TβRII promoter, clearly linking these epigenetic events to KSHV latent infection. In fact, these data add to the growing list of epigenetic events that LANA appears to modulate. Importantly, these findings were extended to primary cases of PEL, KS, and MCD, further extending their biological significance. Interestingly, TβRII was present in a minority of cells expressing LANA in KS and MCD, indicating that the story may be more complicated than it appears at first blush.

These data support a model whereby KSHV LANA thwarts TGF-β signaling in infected cells. The authors show, notably, that re-establishing signaling through this pathway reduced viability of the cells. These findings open up the possibility of a novel avenue for drug development, namely demethylating agents and histone deacetylase inhibitors, for use in the potential treatment of PEL and other KSHV-associated malignancies.