Diergaarde, B. | bioRxiv Science

bioRxiv2019

Alternative Polyadenylation Modifies Target Sites of MicroRNAs with Clinical Potential for Breast Cancer Progression

BackgroundAlternative polyadenylation (APA) shortens or lengthens the 3-untranslated region (3-UTR) of hundreds of genes in cancer. While APA genes modify microRNA target sites in the 3-UTRs to promote tumorigenesis, previous studies have focused on a subset of the modification landscape.\n\nMethodFor comprehensive understanding of the function of global APA events, we consider the total target site landscape of microRNAs that are significantly and collectively modified by global APA genes. To identify such microRNAs in spite of complex interactions between microRNAs and the APA genes, we developed Probabilistic Inference of MicroRNA Target Site Modification through APA (PRIMATA-APA).\n\nResultsRunning PRIMATA-APA on TCGA breast cancer data, we identified that global APA events concentrate to modify target sites of particular microRNAs (target-site-modified-miRNA or tamoMiRNA). TamoMiRNAs are enriched for microRNAs known to regulate cancer etiology and treatments. Also, their target genes are enriched in cancer-associated pathways, suggesting that APA modifies target sites of tamoMiRNAs to progress tumors. Knockdown of NUDT21, a master 3-UTR regulator in HeLa cells, confirmed the causal role of tamoMiRNAs for tumor growth.\n\nConclusionsFurther, the expressions of tamoMiRNA target genes, enriched in cancer-associated pathways, vary across tumor samples as a function of patient-specific APA events, suggesting that APA is a novel regulatory axis for interpatient tumor heterogeneity.

bioinformatics↗

bioRxiv2019

3ʹ-UTR shortening disrupts ceRNA crosstalk of housekeeping genes resulting in subtype-specific breast cancer development

Shortening of 3'UTRs (3'US) through alternative polyadenylation (APA) is a post-transcriptional mechanism that regulate expression of hundreds of genes in human cancers. In breast cancer, different subtypes of tumor samples, such as estrogen receptor positive and negative (ER+ and ER-), are characterized by distinct molecular mechanisms, suggesting possible differences in the post-transcriptional regulation between the subtype tumors. In this study, based on the profound tumorigenic role of 3'US interacting with competing-endogenous RNA (ceRNA) network (3'US-ceRNA effect), we hypothesize that the 3'US-ceRNA effect drives subtype-specific tumor growth. However, we found that the subtypes are available in different sample size, biasing the ceRNA network size and disabling the fair comparison of the 3'US-ceRNA effect. Using normalized Laplacian Matrix Eigenvalue Distribution, we addressed this bias and built the tumor ceRNA networks comparable between the subtypes. Based on the comparison, we identified a novel role of housekeeping (HK) genes as stable and strong miRNA sponges (sponge HK genes) that synchronize the ceRNA networks of normal samples (adjacent to ER+ and ER- tumor samples). We further found that distinct 3'US events in the ER- tumor break the stable sponge effect of HK genes in a subtype-specific fashion, especially in association with the aggressive and metastatic phenotypes. Knockdown of NUDT21, a master 3'-UTR regulator in HeLa cells, confirmed the causal role of 3'US-ceRNA effect repressing HK genes for tumor growth. In this study, we identified 3'US-ceRNA effect on the sponge HK genes for subtype-specific growth of ER- tumors.

cancer biology↗