TARBP2 binding to sRSEs within metastasis suppressor transcripts promotes their decay.

  • Major finding: TARBP2 binding to sRSEs within metastasis suppressor transcripts promotes their decay.

  • Mechanism: TARBP2-driven breast cancer metastasis requires destabilization of the APP and ZNF395 transcripts.

  • Impact: Noncanonical pathways of post-transcriptional control can contribute to cancer progression.

Deregulated post-transcriptional control has been linked to cancer progression. To examine whether structural mRNA elements also contribute to tumorigenesis, Goodarzi and colleagues measured the decay rates of approximately 13,000 transcripts expressed in weakly and highly metastatic isogenic breast cancer cell lines. Computational analysis highlighted a family of GC-rich, cis-regulatory structural RNA stability elements (sRSE) located in transcripts with reduced stability in highly metastatic cells. Titration with a synthetic sRSE-containing RNA oligonucleotide induced stabilization of endogenous sRSE-containing transcripts, and addition of an sRSE was sufficient to reduce transcript expression in a structure-dependent manner. A computational search for RNA-binding proteins whose expression was correlated with sRSE-containing transcript levels identified TAR (HIV-1) RNA-binding protein 2 (TARBP2), a double-stranded RNA-binding protein implicated in miRNA processing, as the sRSE-binding trans factor. Indeed, suppression of TARBP2 led to upregulation of sRSE-containing transcripts via enhanced transcript stability. TARBP2 interacted with a set of transcripts termed TARBP2-binding structural elements that were differentially destabilized in highly metastatic cells. Consistent with a potential role for TARBP2 in metastasis, TARBP2 expression was elevated in metastatic breast cancer cell lines and metastatic primary human breast tumors, and suppression of TARBP2 inhibited the metastatic potential of breast cancer cells in vivo without affecting primary tumor growth. Gene expression and transcript stability analyses identified amyloid precursor protein (APP) and the transcription factor zinc finger protein 395 (ZNF395) as TARBP2-repressed transcripts and showed that reduced expression of these genes was correlated with high-grade tumors and reduced metastasis-free survival. Importantly, silencing of APP and ZNF395 enhanced invasion and metastatic colonization in TARBP2-depleted cells, implicating these genes as metastasis suppressors in breast cancer; addition of the APP cleavage peptide amyloid-α decreased cancer cell invasion, whereas ZNF395 knockdown derepressed the expression of prometastatic genes. Together, these results define a noncanonical TARBP2-driven mechanism of post-transcriptional regulation that contributes to metastatic progression.

Goodarzi H, Zhang S, Buss CG, Fish L, Tavazoie S, Tavazoie SF. Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins. Nature 2014 Jul 9 [Epub ahead of print].

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