Like tiny pirates commandeering a host cell ship, viruses invade and divert cell resources to themselves. This often includes suppressing host gene expression in favor of viral gene expression. While this suppression is detrimental to healthy cells, for cancer cells — with their runaway cellular replication and proliferation characteristics — viral proteins may present a clever treatment strategy.
In a new study published in Communications Biology, scientists at the University of California, Davis isolated a peptide derived from Kaposi’s sarcoma-associated herpesvirus (KSHV) that kills lymphoma cells in culture and in a mouse lymphoma tumor model (1). The peptide downregulates inflammatory response pathway gene expression and blocks the expression of MYC, a transcription factor that controls growth and cell cycle entry, likely contributing to the peptide’s anti-cancer effect.
“It makes sense that shutting down MYC is actually an essential step for this process because MYC is such a key master regulator of cell proliferation that it's shutdown is instrumental for the viral objective,” said Laura Soucek, a cancer researcher who develops MYC inhibitors at the Vall d’Hebron Institute of Oncology who was not involved in the study.
The KSHV transcription factor K-Rta triggers the transition from latency, where the virus lies dormant in human cells, to active viral gene transcription, redirecting the majority of host cell transcriptional machinery from producing host proteins to viral particles (2). Yoshihiro Izumiya, a virologist at the University of California, Davis and senior author of the study, wondered if K-Rta could be used to control gene expression in cancer cells where it would be beneficial to downregulate transcription.
In a collaboration with immunologist Michiko Shimoda at the University of California, Davis, Izumiya and his team discovered that K-Rta’s intrinsically disordered region (IDR) directly interacts with the proteins involved in DNA replication and transcription, including RNA Polymerase II and components of the SWI/SNF chromatin remodeling complex, an important gene expression regulator. They synthesized a peptide containing the K-Rta IDR region and named it Virus de Gann wo Naosu ORF50 (VGN50), which translates from Japanese as “curing cancers with viral proteins.” VGN50 inhibited the growth of leukemia and lymphoma cancer cells in vitro and reduced lymphoma tumor size in a mouse.
RNA sequencing of lymphoma cells treated with VGN50 revealed that the peptide induced a down-regulation of alpha and gamma interferon pathway genes, MYC-target gene expression, and MYC expression itself.
“We didn't really expect to specifically target MYC, but in the end we saw in the genomic study that MYC is our main target,” said Izumiya.
VGN50 treatment of lymphoma cells decreased the presence of MYC-regulating proteins at their normal binding sites, and in vitro experiments demonstrated that VGN50 directly bound to the SWI/SNF complex.
The results suggest a model where VGN50 adheres to and sequesters host cell proteins like the SWI/SNF complex such that these gene expression activating complexes can no longer bind to the MYC promoter region to induce transcription.
“The fact that they've managed to identify a specific peptide that seems responsible for this activity on the MYC promoter is really particularly interesting,” said Soucek.
She also stressed caution in referring to VGN50 as a MYC inhibitor. “The problem here is MYC specificity. Whatever they have is something very interesting that impinges on MYC, but it's not a direct inhibitor,” she explained. For example, the SWI/SNF complex activates thousands of genes in a cell, so by binding SWI/SNF, VGN50 inhibits the activation of all SWI/SNF-regulated genes, including MYC.
Soucek found VGN50’s downregulation of interferon gamma and alpha pathway components intriguing. She suggested that this anti-inflammatory effect might also contribute to VGN50’s anti-cancer activity.
Izumiya and his team are focusing on how best to deliver VGN50 to cancer cells. They hope to partner with others working on MYC inhibitors to bring their peptide closer to the clinic.
In the meantime, Izumiya and Shimoda have identified other viral proteins that target specific processes in host cells. They plan to investigate these viral players to characterize their therapeutic potential.
References
- Shimoda, M. et al. KSHV transactivator-derived small peptide traps coactivators to attenuate MYC and inhibits leukemia and lymphoma cell growth. Commun Biol 4, 1330 (2021).
- Lukac, D.M. et al. Transcriptional Activation by the Product of Open Reading Frame 50 of Kaposi’s Sarcoma-Associated Herpesvirus Is Required for Lytic Viral Reactivation in B Cells. Journal of Virology 73, 9348-9361 (1999).
