Associating lncRNAs with small molecules via bilevel optimization reveals cancer-related lncRNAs

Abstract

Long noncoding RNA (lncRNA) transcripts have emerging impacts in cancer studies, which suggests their potential as novel therapeutic agents. However, the molecular mechanism behind their treatment effects is still unclear. Here, we designed a computational model to Associate LncRNAs with Anti-Cancer Drugs (ALACD) based on a bilevel optimization model, which optimized the gene signature overlap in the upper level and imputed the missing lncRNA-gene association in the lower level. ALACD predicts genes coexpressed with lncRNAs mean while matching drug's gene signatures. This model allows us to borrow the target gene information of small molecules to understand the mechanisms of action of lncRNAs and their roles in cancer. The ALACD model was systematically applied to the 10 cancer types in The Cancer Genome Atlas (TCGA) that had matched lncRNA and mRNA expression data. Cancer type-specific lncRNAs and associated drugs were identified. These lncRNAs show significantly different expression levels in cancer patients. Follow-up functional and molecular pathway analysis suggest the gene signatures bridging drugs and lncRNAs are closely related to cancer development. Importantly, patient survival information and evidence from the literature suggest that the lncRNAs and drug-lncRNA associations identified by the ALACD model can provide an alternative choice for cancer targeting treatment and potential cancer pognostic biomarkers. The ALACD model is freely available at https://github.com/wangyc82/ALACD-v1.

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“…However, finding small molecules that interact with lncRNA is challenging compared to the case of the well-studied miRNAs, due in part to the low levels of lncRNA expression in cells. 73 Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA that functions in the nucleus as a molecular skeleton for ribonucleoprotein complexes. 74,75 MALAT1 has roles in tumor cell proliferation, migration, invasion, and apoptosis and is considered a potential therapeutic target.…”

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