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

AbstractIn 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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KSHV transactivator-derived small peptide traps coactivators to attenuate MYC function and kills leukemia and lymphoma

10.21203/rs.3.rs-957900/v1 ◽

2021 ◽

Author(s):

Michiko Shimoda ◽

Yuanzhi Lyu ◽

Kang-Hsin Wang ◽

Ashish Kumar ◽

Hiroki Miura ◽

...

Keyword(s):

Gene Expression ◽

Tissue Culture ◽

Target Gene ◽

Primary Effusion Lymphoma ◽

Xenograft Tumor ◽

Small Peptide ◽

Nuclear Receptor Coactivator ◽

Viral Peptide ◽

Tumor Mouse Model ◽

Cell Gene

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 identified a small peptide derived from the Kaposi's sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular c-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 confirmed 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 have significant potential as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases.

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Inactivating Gene Expression with Antisense Modified Oligonucleotides

Acta Naturae ◽

10.32607/actanaturae.11522 ◽

2021 ◽

Vol 13 (3) ◽

pp. 101-105

Author(s):

Sidney Altman ◽

Carlos Angele-Martinez

Keyword(s):

Gene Expression ◽

Tissue Culture ◽

Plasmodium Falciparum ◽

Human Tissue ◽

Target Gene ◽

Modified Oligonucleotides ◽

Modified Nucleotides ◽

Culture Cells ◽

Tissue Culture Cells

Modified nucleotides, including phosphoramidates and mesyl nucleotides, are very effective in inactivating gene expression in bacteria. Gyr A is the target gene in several organisms, including Plasmodium falciparum. Antisense reactions with bacteria infecting citrus plants are promising but incomplete. Human tissue culture cells assayed with a different target are also susceptible to the presence of mesyl oligonucleotides.

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Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

Nature Communications ◽

10.1038/s41467-020-20136-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Chong Wang ◽

Luyao Zhang ◽

Liangru Ke ◽

Weiyue Ding ◽

Sizun Jiang ◽

...

Keyword(s):

Gene Expression ◽

Cell Growth ◽

Cell Line ◽

Poor Prognosis ◽

Target Gene ◽

Primary Effusion Lymphoma ◽

Knock Out ◽

Growth And Survival ◽

Super Enhancer ◽

Genome Wide

AbstractPrimary effusion lymphoma (PEL) has a very poor prognosis. To evaluate the contributions of enhancers/promoters interactions to PEL cell growth and survival, here we produce H3K27ac HiChIP datasets in PEL cells. This allows us to generate the PEL enhancer connectome, which links enhancers and promoters in PEL genome-wide. We identify more than 8000 genomic interactions in each PEL cell line. By incorporating HiChIP data with H3K27ac ChIP-seq data, we identify interactions between enhancers/enhancers, enhancers/promoters, and promoters/promoters. HiChIP further links PEL super-enhancers to PEL dependency factors MYC, IRF4, MCL1, CCND2, MDM2, and CFLAR. CRISPR knock out of MEF2C and IRF4 significantly reduces MYC and IRF4 super-enhancer H3K27ac signal. Knock out also reduces MYC and IRF4 expression. CRISPRi perturbation of these super-enhancers by tethering transcription repressors to enhancers significantly reduces target gene expression and reduces PEL cell growth. These data provide insights into PEL molecular pathogenesis.

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