Regulation of Epithelial-to-Mesenchymal Transition by Alternative Translation Initiation Mechanisms and Its Implications for Cancer Metastasis - PubMed (original) (raw)

Review

Regulation of Epithelial-to-Mesenchymal Transition by Alternative Translation Initiation Mechanisms and Its Implications for Cancer Metastasis

Amit Bera et al. Int J Mol Sci. 2020.

Abstract

Translation initiation plays a critical role in the regulation of gene expression for development and disease conditions. During the processes of development and disease, cells select specific mRNAs to be translated by controlling the use of diverse translation initiation mechanisms. Cells often switch translation initiation from a cap-dependent to a cap-independent mechanism during epithelial-to-mesenchymal transition (EMT), a process that plays an important role in both development and disease. EMT is involved in tumor metastasis because it leads to cancer cell migration and invasion, and is also associated with chemoresistance. In this review we will provide an overview of both the internal ribosome entry site (IRES)-dependent and N6-methyladenosine (m6A)-mediated translation initiation mechanisms and discuss how cap-independent translation enables cells from primary epithelial tumors to achieve a motile mesenchymal-like phenotype, which in turn drives tumor metastasis.

Keywords: IRES; ITAF; cancer; epithelial-to-mesenchymal transition (EMT); m6A-mediated translation; metastasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Overview of internal ribosome entry site (IRES)-mediated translation initiation. The requirement for canonical initiation factors and IRES trans-acting factors (ITAFs) varies among IRES-containing mRNAs. Several types of IRES-mediated translation initiation have been identified: (A) Group I: no canonical factors are required and the 40S ribosome is directly recruited to the mRNA by the IRES structure; (B) Group II: a few canonical initiation factors are required for 40S ribosome recruitment; (C) Groups III and IV: multiple canonical initiation factors, as well as ITAFs, are required for 40S ribosome recruitment and translation initiation.

Figure 2

Overview of the role of N6-methyladenosine (m6A) modification of mRNA in protein synthesis. m6A modification of mRNA within the 5ʹ untranslated region (5ʹ-UTR) permits direct binding of the eIF3 complex to facilitate recruitment of the 43S pre-initiation complex, which mediates translation initiation. m6A modification within the coding sequence can enhance recruitment of the eEF-2 elongation factor via YDHTF1 binding to the m6A residue, which enhances translation of the mRNA.

Figure 3

Alternative translation mechanisms are involved in the synthesis of proteins with roles in epithelial-to-mesenchymal transition (EMT). (A) The YB-1 protein recruits the translation initiation machinery to mRNAs that encode Snail1, ZEB2, and HIF-1α to support their synthesis, leading to EMT. (B) Reduced expression of the initiation factor eIF3e facilitates the translation of the Snail1 and ZEB2 proteins to mediate EMT. (C) The ITAF La mediates the translation of Laminin B1 to drive cells toward EMT. (D) m6A modifications within the Snail1 open reading frame permit enhanced recruitment of the elongation factor eEF-2 via YTHDF1 to increase Snail 1 translation and facilitate EMT.

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Regulation of Epithelial-to-Mesenchymal Transition by Alternative Translation Initiation Mechanisms and Its Implications for Cancer Metastasis - PubMed (original) (raw)