The lncRNA KTN1-AS1 co-regulates a variety of Myc-target genes and enhances proliferation of Burkitt lymphoma cells

Melanie Winkle*, Mina M Tayari, Klaas Kok, Gerben Duns, Natalia Grot, Marta Kazimierska, Annika Seitz, Debora Jong, Jasper Koerts, Arjan Diepstra, Agnieszka Dzikiewicz-Krawczyk, Christian Steidl, Joost Kluiver, Anke van den Berg

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

8 Citaten (Scopus)
104 Downloads (Pure)

Samenvatting

Long noncoding RNAs (lncRNAs) are involved in many normal and oncogenic pathways through a diverse repertoire of transcriptional and posttranscriptional regulatory mechanisms. LncRNAs that are under tight regulation of well-known oncogenic transcription factors such as c-Myc (Myc) are likely to be functionally involved in their disease-promoting mechanisms. Myc is a major driver of many subsets of B cell lymphoma and to date remains an undruggable target. We identified three Myc-induced and four Myc-repressed lncRNAs by use of multiple in vitro models of Myc-driven Burkitt lymphoma and detailed analysis of Myc binding profiles. We show that the top Myc-induced lncRNA KTN1-AS1 is strongly upregulated in different types of B cell lymphoma compared to their normal counterparts. We used CRISPR-mediated genome editing to confirm that the direct induction of KTN1-AS1 by Myc is dependent on the presence of a Myc E-box-binding motif. Knockdown of KTN1-AS1 revealed a strong negative effect on the growth of three BL cell lines. Global gene expression analysis upon KTN1-AS1 depletion shows a strong enrichment of key genes in the cholesterol biosynthesis pathway as well as co-regulation of many Myc-target genes, including a moderate negative effect on the levels of Myc itself. Our study suggests a critical role for KTN1-AS1 in supporting BL cell growth by mediating co-regulation of a variety of Myc-target genes and co-activating key genes involved in cholesterol biosynthesis. Therefore, KTN1-AS1 may represent a putative novel therapeutic target in lymphoma.

Originele taal-2English
Pagina's (van-tot)4193-4206
Aantal pagina's14
TijdschriftHuman Molecular Genetics
Volume31
Nummer van het tijdschrift24
Vroegere onlinedatum22-jul.-2022
DOI's
StatusPublished - dec.-2022

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