Muscleblind‑like 1 destabilizes Snail mRNA and suppresses the metastasis of colorectal cancer cells via the Snail/E‑cadherin axis

Abstract

RNA-binding proteins (RBPs) play a fundamental role in the recurrence and metastasis of colorectal cancer (CRC). In this study, we identified muscleblind-like 1 (MBNL1), an RBP implicated in developmental control, as a robust suppressor of CRC cell metastasis in vitro. By using a scratch assay coupled with time-lapse live cell imaging, our findings revealed that the knockdown of MBNL1 induced epithelial-to-mesenchymal transition (EMT)-like morphological changes in the HCT-116 cells, accompanied by an enhanced cell motility, and by the downregulation of E-cadherin and the upregulation of Snail expression. By contrast, the ectopic overexpression of MBNL1 suppressed EMT, characterized by the upregulation of E-cadherin and the downregulation of Snail expression. Mechanistically, Snail rather than E-cadherin, was identified as a direct downstream target gene of MBNL1. The ectopic the overexpression of MBNL1 markedly enhanced the recruitment of Snail transcripts to processing bodies (P-bodies), leading to the increased degradation of Snail mRNA and consequent translational silencing. Furthermore, the effect of MBNL1 on CRC cell migration was confirmed in additional CRC cell lines. SW480 and HT-29 cells exhibited similar changes in migratory capacity and the expression of Snail/E-cadherin to those observed in HCT-116 cells. On the whole, this study demonstrates that MBNL1 destabilizes Snail transcripts and, in turn, suppresses the EMT of CRC cells through the Snail/E-cadherin axis in vitro. Therefore, this EMT-related MBNL1/Snail/E-cadherin axis may prove to be a novel therapeutic target for CRC metastasis.

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

“…It has been shown that MBNL1 suppresses breast cancer metastatic colonization through regulating transcript stabilization 18 . A recent study showed that MBNL1 inhibited colorectal cancer metastasis by modulation of the Snail/E-cadherin axis 19 . Furthermore, another family member MBNL3, was found to act as an oncogene, because it promoted tumorigenesis and its high expression indicated poor prognosis in hepatocellular carcinoma 20 .…”

The SRSF3-MBNL1-Acin1 circuit constitutes an emerging axis to lessen DNA fragmentation in colorectal cancer via an alternative splicing mechanism

“…MBNL1 was demonstrated to be a master splicing regulator for shaping transcriptomic profiles throughout the development of striated muscle and blood lineages [42 , 43] . Even though the tumor-suppressive influence of MBNL1 toward cancer cells via AS regulation was recently revealed [23] , the MBNL1 isoform was reported to exert an opposite effect on carcinogenic signatures [24] . The presence of the MBNL1 isoform lacking exon 7 was shown to cause DNA damage, which in turn interfered with cell viability and migration [24] .…”

“…In addition to the molecular mechanism involved in regulating MBNL1 and MBNL1-mediated impacts on tissue development, its influence on carcinogenesis was recently investigated. MBNL1 exerted potential effect on suppressing the progression of breast cancer and CRC possibly through AS regulation [22] , [23] , [24] .…”

Systematic Expression Analysis of Zinc-finger Transcription Factor Family Reveals the Importance of Snai1 in Colorectal Carcinogenesis

“…Colorectal cancer is one of the most common malignant tumors of the digestive system, with more than 1.8 million newly diagnosed cases and 800,000 cancer related deaths around the world in 2018 [1]. In addition to tumorigenesis, tumor metastasis seems to be another important cause of cancer related death in patients with CRC [30]. Despite the treatment of cancer has made great progress in recent years, the underlying molecular mechanisms of tumorigenesis and metastasis are complex and worthy of further study.…”