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.
Highlights
In herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors
We previously reported that when Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation begins, RNA Polymerase II (RNAPII) molecules are effectively recruited to viral episomes and form a complex with a viral protein, KSHV replication and transactivation (K-Rta), for viral gene expression[36]
We examined cellular proteins that are localized in the RNA polymerase II (RNAPII) and Kaposi’s sarcoma-associated herpesvirus transactivator (K-Rta) protein complex during KSHV reactivation by utilizing rapid immunoprecipitation mass spectrometry of endogenous protein (RIME)[40]
Summary
Host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors. 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. Small molecule inhibitors targeting the respective enzyme pockets or acetylated histone binding surfaces have all shown some efficacies against MYC, with BET inhibitors being the most well-studied[6,7,8,9,10,11]. The mimetic small molecule competes with BET proteins (mainly BRD2 and 4) for binding to the acetylated histone tail, and pharmacological inhibition of BET proteins shows therapeutic activity in a variety of pathologies, in models of cancer and inflammation[11,13,14,15]. Isolating and manipulating such a specific viral protein functional domain may be used as a competitor to attenuate cellular protein functions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
