AN ONCOGENIC ISOFORM SWITCH LEADS TO HNRNPA1 OVEREXPRESSION IN TRIPLE NEGATIVE BREAST CANCER

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2022-8-05
Erdem, Murat
HNRNPA1 is one of the most abundant and ubiquitously expressed nuclear proteins and plays a significant role in RNA biology. It has many diverse functions in cellular nucleic acid metabolisms, including mRNA transport, miRNA maturation, and telomere maintenance. Emerging evidence suggest HNRNPA1 to be an important RNA binding protein (RBP) to regulate various RNA related processes in cancer cells. However, deregulation of HNRNPA1 expression and its action mechanisms are unclear in breast cancers. The study aims to investigate the isoform level expression of HNRNPA1 and the role of HNRNPA1 in breast cancer models. Using expression data in GTEx and TCGA databases, and microarray data set, an isoform switch between the 3'UTR isoforms of HNRNPA1 was discovered in breast cancers. It is shown that the mammary tissue has a dominantly expressed isoform with a short half-life. On the other hand, this isoform is downregulated in breast cancers, favoring a much more stable isoform. It is shown that the overexpression of this stable isoform leads to increased HNRNPA1 protein levels. In turn, high HNRNPA1 protein levels correlate with poor survival in patients. In support of this, silencing of HNRNPA1 causes a reversal in neoplastic phenotypes, including proliferation, clonogenic potential, migration, and invasion. In addition, silencing of HNRNPA1 results in the downregulation of microRNAs that map to intragenic regions. Among the downregulated miRNAs, pri-miR-27b and its host gene (C9ORF3) expression were decreased, suggesting that pri-miR-27b and C9ORF3 expressions were co-regulated by HNRNPA1 at the transcriptional level in MDA-MB-231 cells. In summary, a cancer-specific isoform switch was identified for HNRNPA1 and a novel insight was provided on the function of HNRNPA1 in breast cancers.

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Citation Formats
M. Erdem, “AN ONCOGENIC ISOFORM SWITCH LEADS TO HNRNPA1 OVEREXPRESSION IN TRIPLE NEGATIVE BREAST CANCER,” Ph.D. - Doctoral Program, Middle East Technical University, 2022.