lncRNA Directs Cooperative Epigenetic Regulation Downstream of Chemokine Signals

• BCAR4 is a TNBC-upregulated lncRNA that is essential for breast cancer metastasis
• BCAR4 functions downstream of a CCL21-triggered noncanonical Hedgehog pathway
• BCAR4 binds SNIP1 and PNUTS to mediate epigenetic activation of GLI2 target genes
• In vivo targeting of BCAR4 by LNA therapeutically inhibits breast cancer metastasis

SummarylncRNAs are known to regulate a number of different developmental and tumorigenic processes. Here, we report a role for lncRNA BCAR4 in breast cancer metastasis that is mediated by chemokine-induced binding of BCAR4 to two transcription factors with extended regulatory consequences. BCAR4 binding of SNIP1 and PNUTS in response to CCL21 releases the SNIP1’s inhibition of p300-dependent histone acetylation, which in turn enables the BCAR4-recruited PNUTS to bind H3K18ac and relieve inhibition of RNA Pol II via activation of the PP1 phosphatase. This mechanism activates a noncanonical Hedgehog/GLI2 transcriptional program that promotes cell migration. BCAR4 expression correlates with advanced breast cancers, and therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 strongly suppresses breast cancer metastasis in mouse models. The findings reveal a disease-relevant lncRNA mechanism consisting of both direct coordinated protein recruitment and indirect regulation of transcription factors.

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