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

  • Author(s): Shimoda, Michiko;
  • Lyu, Yuanzhi;
  • Wang, Kang-Hsin;
  • Kumar, Ashish;
  • Miura, Hiroki;
  • Meckler, Joshua F;
  • Davis, Ryan R;
  • Chantarasrivong, Chanikarn;
  • Izumiya, Chie;
  • Tepper, Clifford G;
  • Nakajima, Ken-Ichi;
  • Tuscano, Joseph;
  • Barisone, Gustavo;
  • Izumiya, Yoshihiro
  • et al.
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.

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