Quaking 5 suppresses TGF‐β‐induced EMT and cell invasion in lung adenocarcinoma

Abstract

Quaking (QKI) proteins belong to the signal transduction and activation of RNA (STAR) family of RNA-binding proteins that have multiple functions in RNA biology. Here, we show that QKI-5 is dramatically decreased in metastatic lung adenocarcinoma (LUAD). QKI-5 overexpression inhibits TGF-b-induced epithelialmesenchymal transition (EMT) and invasion, whereas QKI-5 knockdown has the opposite effect. QKI-5 overexpression and silencing suppresses and promotes TGF-b-stimulated metastasis in vivo, respectively. QKI-5 inhibits TGF-b-induced EMT and invasion in a TGFbR1-dependent manner. KLF6 knockdown increases TGFbR1 expression and promotes TGF-b-induced EMT, which is partly abrogated by QKI-5 overexpression. Mechanistically, QKI-5 directly interacts with the TGFbR1 3 0 UTR and causes post-transcriptional degradation of TGFbR1 mRNA, thereby inhibiting TGF-b-induced SMAD3 phosphorylation and TGF-b/SMAD signaling. QKI-5 is positively regulated by KLF6 at the transcriptional level. In LUAD tissues, KLF6 is lowly expressed and positively correlated with QKI-5 expression, while TGFbR1 expression is up-regulated and inversely correlated with QKI-5 expression. We reveal a novel mechanism by which KLF6 transcriptionally regulates QKI-5 and suggest that targeting the KLF6/QKI-5/TGFbR1 axis is a promising targeting strategy for metastatic LUAD.

RNA demethylase ALKBH5 inhibits TGF‐β‐induced EMT by regulating TGF‐β/SMAD signaling in non‐small cell lung cancer

“…This point was further strengthened by the evidence that ALKBH5 dramatically inhibited TGF-βinduced upregulation of p-SMAD3 (Supporting Information Figure S3), a hallmark of TGF-β/SMAD activation. 36,37 Combining with our previous findings that TGF-β/SMAD signaling activation promotes TGF-βinduced EMT in NSCLC cells, 8,9 the present data suggest that ALKBH5 suppresses TGF-βinduced EMT by erasing m 6 A modification of TGF-β/SMAD signaling components and inhibitory regulator, including TGFβR2/SMAD3 and SMAD6. Of course, we can′t exclude ALKBH5-mediated m 6 A demethylation of other signaling pathways affecting TGF-βinduced EMT (Figure 4D).…”

“…Considering that TGF‐β signaling‐mediated EMT is involved in NSCLC metastasis, 8,9 we performed gene set enrichment analysis (GSEA) based on http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc%3DGSE19804 from GEO database to predict whether ALKBH5 may regulate TGF‐β signaling‐mediated EMT. Notably, GSEA showed that three gene sets, including epithelial cell migration, EMT and TGF‐β signaling pathway, were dramatically enriched in NSCLC patients with low ALKBH5 expression (Figure 1D–F).…”

“…7 We previously reported that TGF-β/SMAD signaling activation can promote TGF-βinduced EMT in NSCLC cells. 8,9 In the canonical TGF-β/SMAD signal transduction, TGF-β receptor type II (TGFβR2) cooperates with TGFβR1, SMAD2/3 (R-SMADs) and SMAD4 (Co-SMAD) to activate the pathway and thereby regulating downstream target genes. In the nucleus, TGF-βinduced SMAD3/4 complex may transactivate a series of EMT-related genes.…”

Tetraspanin 1 (TSPAN1) promotes growth and transferation of breast cancer cells via mediating PI3K/Akt pathway

“…TSPAN1 promoted EMT and metastasis of cholangiocarcinoma by activating PI3K/AKT pathway, and we also revealed a similar mechanism in breast cancer [ 18 ]. EMT causes tumor epithelial cells to lose their polarity, converts adherent phenotypes into mesenchymal forms, and increases the ability of cancer cells to invade and migrate [ 28 ]. EMT also plays a key role in the metastasis of malignant tumor cells [ 29 ].…”

Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling

“…The EMT that is associated with TGF-β/Smads signaling can be suppressed by lncRNA Smad3-associated long non-coding RNA (SMASR), which are close to Smad3 in lung cancer cells [ 93 ]. Similarly, in lung cancer cells, TGF-β induced EMT could also be suppressed by quaking 5 (QKI-5) protein via binding directly to the 3′UTR region of TGFR1 to degrade its mRNA [ 94 ].…”