In a study reported in Nature, Goodarzi and colleagues attempted to identify post-transcriptional modulators of mRNA stability in breast cancer via whole-genome transcript stability measurements in poorly and highly metastatic isogenic human breast cancers. They identified a family of structural RNA stability elements (sRSEs) that were overrepresented in transcripts with reduced stability in highly metastatic cells. They further found that TARBP2, a double-stranded RNA-binding protein involved in microRNA processing, was the trans factor binding the sRSE family and similar structural elements—TARBP2-binding structural elements (TBSEs)—within transcripts.
TARBP2 was overexpressed in metastatic cells and metastatic breast tumors and was found to destabilize transcripts containing TBSEs. The protein promoted metastatic cell invasion and colonization by destabilizing transcripts of amyloid precursor protein (APP) and ZNF395 genes (previously associated with Alzheimer’s and Huntington’s disease). The cleavage product of APP, extracellular amyloid-α peptide, was found to directly inhibit invasion and ZNF395 was shown to transcriptionally inhibit a gene expression program that supports metastasis. Analysis of expression levels in breast carcinomas supported the roles of TARBP2, APP and ZNF395 in metastasis.
The investigators concluded, “Our findings establish a non-canonical and direct role for TARBP2 in mammalian gene expression regulation and reveal that regulated RNA destabilization through protein-mediated binding of mRNA structural elements can govern cancer progression.” ■
Goodarzi H, et al: Nature. July 9, 2014 (early release online).
