Regulation of the Expression of Cytoplasmic Polyadenylation Element Binding Proteins for the Treatment of Cancer

Abstract

Abstract. Regulated mRNA translation plays an important role in normal cellular functions and cytoplasmic polyadenylation element binding proteins (CPEBs) are the key factors that control the elongation of poly(A) tail during translation. The expression of various Translation and Cytoplasmic Polyadenylation Element Binding Proteins (CPEBs)Regulated mRNA translation plays an important role in normal cellular functions (1, 2). The translation of an mRNA is divided into three steps: initiation, elongation and termination (1). Among them, translation initiation is the rate-limiting, the most complex and the main target for translational control mechanisms (3). The 5'end of all transcribed mRNAs contains a 5'cap and the other end is blocked by a long stretch, usually in the order of 200-500 nucleotides of adenine residues (poly(A) tail) (1). Both the cap and the poly(A) tail of mRNAs act synergistically to facilitate translation (1). The translation is affected by a number of factors that stimulate or inhibit the translation of specific mRNAs (1, 2). Among these factors, RNAbinding proteins that recognize specific motifs in the 3' untranslated region (3'UTR) of their targets, are important (1, 2, 4). Of these RNA-binding proteins, cytoplasmic polyadenylation element binding protein (CPEB) family are sequence-specific RNA-binding proteins and the key factors controling the elongation of the poly(A) tail and polyadenylation-induced translation (2,5,6). CPEB binds the cytoplasmic polyadenylation element (CPE) in the 3' untranslated regions of responding mRNAs (2, 7-9). CPEB-mediated effects on translation require at least two CPEs separated by less than 50 nucleotides in the target mRNA, which indicates the formation of CPEB-dimer (10). CPEBs can recruit the translational repression or cytoplasmic polyadenylation machineries to their target mRNAs and nucleate a complex of factors that regulates poly(A) elongation through a deadenylating enzyme (1,4,7,(11)(12)(13). 5673

CPEB3-mediated MTDH mRNA translational suppression restrains hepatocellular carcinoma progression

“…CPEBs can modulate translational activation or repression by binding to CPE mainly found in 3′-UTR. Several studies demonstrate that CPEB family members mediate malignant transformation, including glioma, colorectal cancer, and so forth 34 . While our research group firstly reported that CPEB3 involved in the regulation of liver cancer progression 12 .…”

“…Specifically binding to cytoplasmic polyadenylation elements (CPEs), CPEBs can further recruit several functional proteins to regulate the poly(A) tail length of target mRNAs, resulting in translational activation or repression of its targets 5,6 . The C terminus, which includes two RNA recognition motif and a zinc-finger domain, is highly conserved among CPEBs 7 . While the highly variable N terminus containing regulatory sites may contribute to the distinct functions of CPEB family members 4 .…”

“…Despite the structural similarities among CPEBs, the expression of CPEBs in different malignancies is highly variable as well as the functions of CPEBs 8,9 . Evidence has shown that CPEB1 is likely to act as a tumor suppressor, while CPEB2 and CPEB4 seem to be oncogenes 7 .…”

CPEB4 promotes growth and metastasis of gastric cancer cells via ZEB1-mediated epithelial–mesenchymal transition

“…Interestingly, recent studies have revealed that CPEB4 was highly expressed in multiple tumor types and was involved in tumor progression and metastasis. 6 , 7 For example, CPEB4 has been reported to be markedly increased in cancer tissues and be a promising therapeutic target in metastatic colorectal carcinoma. 16 In breast cancer, CPEB4 was distinctly elevated in primary lesions compared with adjacent normal tissues and played a pivotal role in breast cancer invasion and metastasis.…”

“…Cytoplasmic polyadenylation element-binding protein 4 (CPEB4), a typical member of the CPEB family, is a sequence-specific RNA-binding protein and a translational regulator, which has been demonstrated to be selectively overexpressed in various malignancies. 6 Notably particularly, recent studies have reported that CPEB4 functions importantly in cancer cells’ migration and invasion in certain types of cancer, such as glioma and breast cancers, and could be exploited as a target for cancer treatment. 7 – 10 Nevertheless, to our knowledge, the clinical significance and biological function in GC remain undetermined and even less is known about the regulatory mechanism of CPEB4-mediated cancer progression.…”