Abstract
Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.
Highlights
In healthy cells, expression of mRNAs for genes associated with cell survival pathways is maintained at normal levels through tight transcriptional and post-transcriptional mechanisms.In contrast, tumor cells possess abnormally stable mRNAs for various categories of pro-survival genes, including protooncogenes, tumor suppressors, and cytokines
Zinc Finger Protein 36 like 1 (ZFP36L1) was demonstrated as a key regulator of cellular senescence by directly regulating components of the senescence-associated secretory protein (SASP) through post-transcriptional regulation
TTP has been shown to directly regulate Epithelial–mesenchymal transition (EMT) regulators, including ZEB1, SOX9, and MACC1, all of which are known to be downregulated in colorectal carcinomas (CRC)
Summary
Expression of mRNAs for genes associated with cell survival pathways is maintained at normal levels through tight transcriptional and post-transcriptional mechanisms. Regardless of the mechanisms involved, owing to the regulation of a broad range of target mRNAs concurrently, the TTP family RBPs loss can result in significant changes in gene expression and can have dramatic consequences for the development and progression of cancer. Restoring TTP expression suppresses cell proliferation, resistance to apoptosis, and VEGF mRNA [16]. Low TTP-expressing breast cancer and lung adenocarcinoma patients show reduced survival and more aggressive tumors. ARE mRNAs. Poor breast cancer patient survival is significantly associated with low TTP and high mitotic. TTP is significantly reduced in gastric cancer tissues and is associated with invasion, lymph node metastasis, and survival. MiR-29a was up-regulated and TTP downregulated in pancreatic cancer tissues and cell lines. Induced TTP expression reduced cell proliferation, clonogenic growth, and tumorigenic potential of prostate cancer cells [64]. ZFP36L2 was identified as a part of gene-regulatory network involved in endodermal carcinogenesis and validated in cellular and mouse models of thyroid cancer [72]
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