Selective Small-Molecule Targeting of a Triple Helix Encoded by the Long Noncoding RNA, MALAT1

Abulwerdi, F. A., Xu, W., Ageeli, A. A., Yonkunas, M. J., Arun, G., Nam, H., Schneekloth, J. S., Dayie, T. K., Spector, D., Baird, N., Le Grice, S. F. J. (February 2019) Selective Small-Molecule Targeting of a Triple Helix Encoded by the Long Noncoding RNA, MALAT1. ACS Chemical Biology, 14 (2). pp. 223-235. ISSN 15548929 (ISSN)

URL: https://www.ncbi.nlm.nih.gov/pubmed/30620551
DOI: 10.1021/acschembio.8b00807

Abstract

Metastasis-associated lung adenocarcinoma transcript 1 (Malat1/MALAT1, mouse/human), a highly conserved long noncoding (lnc) RNA, has been linked with several physiological processes, including the alternative splicing, nuclear organization, and epigenetic modulation of gene expression. MALAT1 has also been implicated in metastasis and tumor proliferation in multiple cancer types. The 3′ terminal stability element for nuclear expression (ENE) assumes a triple-helical configuration that promotes its nuclear accumulation and persistent function. Utilizing a novel small molecule microarray strategy, we identified multiple Malat1 ENE triplex-binding chemotypes, among which compounds 5 and 16 reduced Malat1 RNA levels and branching morphogenesis in a mammary tumor organoid model. Computational modeling and Förster resonance energy transfer experiments demonstrate distinct binding modes for each chemotype, conferring opposing structural changes to the triplex. Compound 5 modulates Malat1 downstream genes without affecting Neat1, a nuclear lncRNA encoded in the same chromosomal region as Malat1 with a structurally similar ENE triplex. Supporting this observation, the specificity of compound 5 for Malat1 over Neat1 and a virus-coded ENE was demonstrated by nuclear magnetic resonance spectroscopy. Small molecules specifically targeting the MALAT1 ENE triplex lay the foundation for new classes of anticancer therapeutics and molecular probes for the treatment and investigation of MALAT1-driven cancers. © 2019 American Chemical Society.

Item Type: Paper
Subjects: Investigative techniques and equipment > cell culture > cancer organoids
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > long non-coding RNA
diseases & disorders > cancer > cancer types > lung cancer
CSHL Authors:
Communities: CSHL labs > Spector lab
Depositing User: Matthew Dunn
Date: 15 February 2019
Date Deposited: 20 Feb 2019 21:10
Last Modified: 20 Feb 2019 21:10
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37704

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