Abstract
Roles of HNRNPA1 are beginning to emerge in cancers; however, mechanisms causing deregulation of HNRNPA1 function remain elusive. Here, we describe an isoform switch between the 3′-UTR isoforms of HNRNPA1 in breast cancers. We show that the dominantly expressed isoform in mammary tissue has a short half-life. In breast cancers, this isoform is downregulated in favor of a stable isoform. The stable isoform is expressed more in breast cancers, and more HNRNPA1 protein is synthesized from this isoform. 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 these miRNAs, miR-21 is known for its transcriptional upregulation in breast and numerous other cancers. Altogether, the cancer-specific isoform switch we describe here for HNRNPA1 emphasizes the need to study gene expression at the isoform level in cancers to identify novel cases of oncogene activation.
Highlights
Roles of HNRNPA1 are beginning to emerge in cancers; mechanisms causing deregulation of HNRNPA1 function remain elusive
We show that HNRNPA1 isoforms with different 3′UTRs have different half-lives and the cancer-specific isoform switch contributes to increased HNRNPA1 protein abundance in breast cancer cells
Mechanisms leading to alternative processing of mRNAs are gaining more attention as we begin to appreciate the complexities of cancer t ranscriptomes[36,37]
Summary
Roles of HNRNPA1 are beginning to emerge in cancers; mechanisms causing deregulation of HNRNPA1 function remain elusive. Silencing of HNRNPA1 results in the downregulation of microRNAs that map to intragenic regions Among these miRNAs, miR-21 is known for its transcriptional upregulation in breast and numerous other cancers. The cancer-specific isoform switch we describe here for HNRNPA1 emphasizes the need to study gene expression at the isoform level in cancers to identify novel cases of oncogene activation. We provide new insight into HNRNPA1 function in indirectly modulating the expression of intragenic microRNAs such as miR-21, a well-known oncomiR These results emphasize the importance of gene expression analysis at the isoform level in cancer cells, revealing unknown oncogene activation cases with biological impact
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