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

Long non-coding 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...

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Published in:Human molecular genetics 2022-12, Vol.31 (24), p.4193-4206
Main Authors: Winkle, Melanie, Tayari, Mina M, Kok, Klaas, Duns, Gerben, Grot, Natalia, Kazimierska, Marta, Seitz, Annika, de Jong, Debora, Koerts, Jasper, Diepstra, Arjan, Dzikiewicz-Krawczyk, Agnieszka, Steidl, Christian, Kluiver, Joost, van den Berg, Anke
Format: Article
Language:English
Subjects:
Burkitt Lymphoma - genetics
Burkitt Lymphoma - metabolism
Burkitt Lymphoma - pathology
Cell Line, Tumor
Cell Proliferation - genetics
Cholesterol
Gene Expression Regulation, Neoplastic
Humans
Lymphoma, B-Cell
Membrane Proteins - genetics
RNA, Long Noncoding - genetics
RNA, Long Noncoding - metabolism
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Summary:Long non-coding 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 with 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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddac159