TGFβ-induced long non-coding RNA LINC00313 activates Wnt signaling and promotes cholangiocarcinoma

Cholangiocarcinoma (CCA) is a poor prognosis liver cancer characterized by high aggressiveness and resistance to therapy. Long non-coding RNAs (lncRNAs) and signals imposed by oncogenic pathways, such as transforming growth factor {beta} (TGF{beta}), contribute to cholangiocarcinogenesis. Here, we identified LINC00313 lncRNA as a novel target of TGF{beta} signalling in CCA cells. TGF{beta} induced LINC00313 expression in a T{beta}RI/Smad-dependent manner. Gene expression and genome-wide chromatin accessibility profiling revealed that nuclear LINC00313 transcriptionally regulated genes involved in Wnt signalling, such as TCF7. LINC00313 gain-of-function enhanced TCF/LEF-dependent transcription, promoted colony formation in vitro and accelerated tumour growth in vivo. Genes associated with LINC00313 over-expression in human CCA were characterized by KRAS and TP53 mutations and reduced patients overall survival. Mechanistically, actin-like 6A (ACTL6A), a subunit of SWI/SNF chromatin remodelling complex, interacted with LINC00313 and impacted on TCF7 and SULF2 transcription. We propose a model whereby TGF{beta} induces LINC00313 in order to regulate expression of hallmark Wnt pathway genes, in co-operation with SWI/SNF. By modulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.