lncRNA B4GALT1‐AS1 promotes colon cancer cell stemness and migration by recruiting YAP to the nucleus and enhancing YAP transcriptional activity

Abstract

Here, an RNA‐sequencing assay revealed long noncoding RNAs (lncRNAs) with an ectopic expression between colon cancer (CC) and normal colon epithelial cells, in which lncRNA B4GALT1‐AS1 exhibited the highest change. A 3‐(4,5‐dimethythiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay indicated that B4GALT1‐AS1 knockdown had no effect on CC cell viability, however, cell clone formation analysis showed that B4GALT1‐AS1 knockdown attenuated the capacity of cell clone formation. Additionally, gene set enrichment analysis of this data set revealed that positive enrichment of stem cell‐differentiated signatures and negative embryonic stem cell function and adult tissue stem module were observed in CC cells with B4GALT1‐AS1 knockdown. Furthermore, B4GALT1‐AS1 knockdown suppressed the stemness‐marker expression, the ability of cell spheroid formation, and ALDH1 activity in CC cells. Mechanistically, RNA‐sequencing data found that the Hippo pathway in cancer was shown on pathways mostly upregulated by B4GALT1‐AS1 knockdown, and B4GALT1‐AS1 directly bound to the yes‐associated protein (YAP), a downstream executor of the Hippo pathway, and B4GALT1‐AS1 knockdown promoted the nuclear cytoplasm translocation of YAP and decreased YAP transcriptional activity. Notably, YAP overexpression attenuated the inhibitory effects mediated by B4GALT1‐AS1 knockdown. Our results identify the direct binding of lncRNA B4GALT1‐AS1 to YAP, which is responsible for CC cell stemness.

The crosstalk between lncRNAs and the Hippo signalling pathway in cancer progression

“…Recently, lncRNAs are emerging as a critical mediator in a wealth of carcinogenic processes by targeting various downstream executors in Hippo signalling pathways (Figure 2). A number of lncRNAs, including B4GALT1 antisense RNA 1 (B4GALT1‐AS1), 35 gastric cancer high expressed transcript 1 (GHET1) 36 and X‐inactive specific transcript (XIST), 37 were tightly associated with YAP to exert their functions in cancers. Zhang et al 35 found that lncRNA B4GALT1‐AS1 was highly expressed in colon cancer cells by RNA‐seq.…”

“…A number of lncRNAs, including B4GALT1 antisense RNA 1 (B4GALT1‐AS1), 35 gastric cancer high expressed transcript 1 (GHET1) 36 and X‐inactive specific transcript (XIST), 37 were tightly associated with YAP to exert their functions in cancers. Zhang et al 35 found that lncRNA B4GALT1‐AS1 was highly expressed in colon cancer cells by RNA‐seq. Depletion of B4GALT1‐AS1 repressed cancer cell colony formation and stemness.…”

The Long Non-Coding RNA MALAT1 Enhances Ovarian Cancer Cell Stemness by Inhibiting YAP Translocation from Nucleus to Cytoplasm

“…Apart from being regulated by Hippo signaling, YAP is modulated by other pathways, such as, mechanical pressure [ 14 ] and Rho-GTPase [ 15 , 16 ]. Recent works showed that lncRNAs are associated with YAP activity, such as lncRNA B4GALT1-AS1 [ 17 , 18 ], lncRNA TUG1 [ 19 ], and lncRNA THOR [ 20 ], in which YAP transcriptional activity is responsible for lncRNA-mediated regulation on cell stemness; these effects supporting the promoting role of YAP in tumor cell stemness [ 21 , 22 ]. Moreover, it is indicated that MALAT1 induces YAP activity contributing to the stemness-related traits of esophageal squamous cell carcinoma [ 23 ].…”

Elucidation of the mechanism underlying CD44v6‐induced transformation of IEC‐6 normal intestinal epithelial cells

“…Additionally, the growth‐promoting effect of YAP has been shown to be critical for the proliferative response observed during intestinal inflammation as well as in sporadic CRC (Avruch, Zhou, & Bardeesy, ; Taniguchi et al, ). More interestingly, the stemness‐stimulating effect of a long noncoding RNA B4GALT1‐AS1 in human colon cancer cells has been attributed to its direct interaction with YAP, resulting in an enhancement of the transcriptional activity of YAP (Zhang et al, ).…”