KSHV transactivator-derived small peptide traps coactivators to attenuate MYC and inhibits leukemia and lymphoma cell growth

Abstract

In herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors. Here, we show a small peptide derived from the Kaposi’s sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular MYC expression, reduces cell proliferation, and selectively kills cancer cell lines in both tissue culture and a xenograft tumor mouse model. Mechanistically, the peptide functions as a decoy to block the recruitment of coactivator complexes consisting of Nuclear receptor coactivator 2 (NCOA2), p300, and SWI/SNF proteins to the MYC promoter in primary effusion lymphoma cells. Thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM seq) with target-transcriptional analyses further confirm that the viral peptide directly attenuates MYC and MYC-target gene expression. This study thus provides a unique tool to control MYC activation, which may be used as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases.

KSHV Topologically Associating Domains in Latent and Reactivated Viral Chromatin

“…This observation suggested that K-Rta targets the boundaries established by CTCF and SMC1 with open chromatin structures. By targeting the boundaries, it is likely that K-Rta can recruit K-Rta-bound chromatin remodeling factors ( 66 ) to the multiple preassembled genomic regions that frequently tethers stalled RNAPII. In turn, Mediator complex, which is also a part of the K-Rta activation complex ( 66 , 67 ), may help to establish active genomic hubs for future reactivation in de novo infected cells.…”

“…By targeting the boundaries, it is likely that K-Rta can recruit K-Rta-bound chromatin remodeling factors ( 66 ) to the multiple preassembled genomic regions that frequently tethers stalled RNAPII. In turn, Mediator complex, which is also a part of the K-Rta activation complex ( 66 , 67 ), may help to establish active genomic hubs for future reactivation in de novo infected cells. Further studies will be needed to reveal the potential association of the initial burst of viral transcription following de novo infection with the establishment of active latent viral chromatin structure.…”

KSHV Terminal Repeat Regulates Inducible Lytic Gene Promoters

“…We also think large LANA NBs are like a "solar panel" to extract energy by intercepting cellular signaling events via highly concentrated LANA/BRD4 complex at TR. The highly-concentrated IDR proteins would absorb transcription enzymes from nearing cellular transcription factors because affinity of interaction among cellular transcription factors and enzymes (i.e., SWI/SNF) are relatively weak in order to share them among other cellular transcription factors for dose-dependent regulation, except viral transcription factor like K-Rta (54). TR fragments and unstructured acidic repeats in LANA protein seems to be designed to concentrate the protein complex near the KSHV unique protein coding regions.…”

“…Names of previously identified LANA neighboring protein with proximity biotin labeling (24) and K-Rta interacting complex (54), which is recruited to RNAPII during reactivation were collected and visualized with STRING, a public database of known and predicted protein-protein interactions. Dynamic protein interaction among K-Rta and LANA protein complex during reactivation was also visualized with STRING after manually combine proteins names together.…”

KSHV Topologically Associating Domains in Latent and Reactivated Viral Chromatin

“…This observation suggested that K-Rta targets the boundaries established by CTCF and SMC1 with open chromatin structures. By targeting the boundaries, it is likely that K-Rta can recruit K-Rta-bound chromatin remodeling factors (82) to the multiple pre-assembled genomic regions for synchronous activation. In turn, Mediator complex, which is also a part of the K-Rta activation complex (82, 83), may help to establish active genomic hubs for future reactivation.…”