Cancer Letters

Cancer Letters

Volume 496, 1 January 2021, Pages 30-40
Cancer Letters

RNA binding proteins: Linking mechanotransduction and tumor metastasis

https://doi.org/10.1016/j.canlet.2020.09.020Get rights and content

Highlights

  • In this review, we summarized the recent progresses in dissecting the molecular mechanism of mechanotransduction in mammalian cells.

  • The role of mechanotransduction in promoting cancer metastasis was discussed.

  • We focused on RNA binding proteins-mediated regulations on key components of mechanotransduction.

Abstract

Mechanotransduction is the leading cellular process that mammalian cells adopted to receive and respond to various mechanical cues from their local microenvironment. Increasing evidence suggests that mechano-transduction is involved in many physiological and disease conditions, ranging from early embryonic development, organogenesis, to a variety of human diseases including cancer. Mechanotransduction is mediated through several classes of senor proteins on the cell surface, intracellular signaling mediators, and core transcriptional regulation networks. Dissecting the molecular mechanisms regulating mechanotransduction and their association with cancer metastasis has received much attention in recent years. RNA binding proteins (RBPs) are a special group of nucleic acid interacting factors that participate in many important cellular processes. In this review, we would like to summarize recent research progresses in understanding the role of RBPs-mediated regulation in mechanotransduction and cancer metastasis. Those intriguing findings will provide novel insights for the disease and guide the potential development of new therapeutic approaches.

Introduction

One of the most fundamental activities of mammalian cells is their constant interaction with the surrounding microenvironment. Through actin filaments and a series of adaptor proteins, the cells manage to sense mechanical cues, contract forces, interact with the extracellular matrix and change the mechanical stimuli into biochemical signals, of which the whole process is named as mechanotransduction [1]. It has long been recognized that mechanotransduction was involved in many important developmental processes such as planar cell polarity [2], cardiac morphogenesis [3], pattern gene activation and gastrulation, etc [4]. While in recent years, growing evidence suggested that this fundamental cellular activity might also have a strong impact on pathological conditions [5]. Thus, it is of great interest to understand the molecular mechanisms in regulating mechanotransduction and their roles in various human diseases, especially in cancer.

Annually, there are 9.6 million cancer-related deaths worldwide, over 90% of which tumor metastasis was the leading cause [6]. Originally, metastasis was regarded as a late event during carcinogenesis while increasing evidence suggested that cell dissemination might occur much earlier than expected [7]. During metastasis, from initiation, cell dissemination, migration until final invasion and colonization, tumor cells constantly receive and respond to the microenvironment cues. The mechanical properties of the extracellular matrix from both the primary tumor loci and metastatic destiny could strongly influence the tumor progression [8]. Therefore, understanding the regulation of mechanotransduction could bring novel insights into the basic biology of tumor metastasis and may lead to the discovery of new therapeutic targets and the development of innovative treatments.

The cellular proteins participating in mechanotransduction include the core transcriptional regulators, such as YAP/TAZ [9], signaling mediators and their associated pathways, such as AKT, RhoA, PI3K and ERK [10,11], cytoskeleton proteins such as actin filaments and nuclear envelope proteins [5], and sensor proteins and adaptors, including focal adhesion molecules, mechanical channel proteins, etc [12]. Transcriptional regulation of these mechanotransduction proteins is one of the key layers of control in mammalian cells and can be hijacked in cancer cells to support their adaption in primary tumor microenvironment and metastasis to new distant locations [13]. In fact, with the advances in the high-throughput sequencing technology, transcriptome analysis comparing tumor versus normal tissues had revealed the aberrant gene transcription was widely present in various types of cancer, regardless of stages or origin [14]. Therefore, exploring the transcriptional regulation of mechanotransduction genes and dissecting the causal link between changes of mechanical properties in tumor microenvironment and metastasis is of particular interest to the cancer research field.

The transcription of mammalian genes was a tightly regulated process where RNA binding proteins (RBPs) were closely involved. From RNA synthesis to decay, they form various dynamic ribonucleocomplex with their client RNA molecules to control target gene expression. In cancer cells, RBPs were reported to regulate context-dependent alternative splicing [15], which was one of the leading causes of aberrant gene expression and tumorigenesis [16]. Moreover, recent researches suggested that many RBPs could interact with long noncoding RNAs to suppress or enhance target gene transcription [17,18]. Some of these RBPs, such as hnRNPA1 [19] and hnRNPA2 [20], were also involved in phase-separation in the nucleus, while other hnRNPs, such as hnRNPA2B1 and SAFA, could serve as a new class of nuclear innate immune sensors [21]. These findings indicated that the function of RBPs was far more diverse than originally anticipated and worth further efforts to dissect their roles in various physiological and disease settings.

In this review, we would like to focus on the RBP-mediated transcriptional control in mechanotransduction and give selected examples of how these regulations may contribute to tumor metastasis. A clearer picture of the role of RBP-mediated transcriptional control for mechanotransduction genes in cancer metastasis will provide new and important insights into understanding the progression of cancer and may provide the basis for developing new therapeutic approaches.

Section snippets

Mechanotransduction in mammalian cells

In mammals, cell proliferation, migration, and expansion are essential for normal embryonic development, during which cells recognize and process the extracellular cues from microenvironment into biochemical signals, control the dynamics of actin filaments, regulate gene transcription and translation, form and disassemble focal adhesion sites to modulate their adhesion and migration ability [22]. There are different types of cellular proteins which participate in the mechanotransduction (Fig. 1

Control of the core YAP/TAZ transcriptional network

YAP/TAZ are transcriptional co-activators that lack direct DNA binding domains and can shuttle between the cytoplasm and the nucleus [32,33]. Originally recognized as components of the Hippo pathway involved in cell contact inhibition and organ size restriction [34], YAP/TAZ were recently identified as core regulators of mechanotransduction and induction of YAP/TAZ by mechanical cues was found to be independent of Hippo [35]. Activation of YAP/TAZ was detected in many human cancers, such as

Transcriptional regulation of mechanotransduction sensors

Several classes of cell surface proteins, including integrins, selectins, cadherins, and mechanosensitive channels, are the main mechanical sensors to detect biomechanical cues and integrate the physical signals with internal cellular responses, which were heavily regulated in tumor cells. When tumor cells undergo metastasis, three major steps must be accomplished: dissemination from the primary site, intravasation and extravasation, and establishment of distant metastasis [46,47], during which

Regulation of key signaling mediators

Multiple signaling mediators participate in mechanotransduction in mammalian cells, including general kinases ERK, AKT, and GTPase RhoA (Fig. 1). In this review, we would like to focus on a unique kinase, focal adhesion kinase (FAK), which is located in the focal adhesion complex. Focal adhesion is one particular form of integrin adhesome, it refers to the stable integrin-mediated, cell-substrate adhesion structures that anchor the termini of actin filaments (stress fibers) and mediate strong

Regulation of other molecules involved in mechanotransduction

Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is a transmembrane glycoprotein involved in cell-cell adhesion, and its abnormal expression was associated with a variety of human malignancies [130]. Alternative splicing of CEACAM1 pre-mRNA generated two variants characterized by the inclusion (L-isoform) or exclusion (S-isoform) of exon 7. In breast cancer cells, RNA immunoprecipitation of hnRNP L and hnRNP A1 revealed a binding motif located central and 3′ to exon 7 of

Conclusions and future perspectives

As illustrated by the above examples (Table 1), it is becoming evident that RBPs-mediated regulation plays a crucial role in mechanotransduction during cancer metastasis. Through focal adhesion complex, various surface proteins, and receptors, cancer cells could process the environmental mechanical cues into intracellular biochemical signals. Mediated by a series of signaling molecules including FAK, RhoA, ERK and AKT, these biochemical signals were further transmitted into the nucleus where

Author contributions

Y. Z, Z. L conceived the idea and wrote the manuscript.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We thank all the Li Lab members for useful discussions. This work was supported by National Key Research and Development Program of China (2017YFA0104801), China Postdoctoral Science Foundation (2020M673209), Postdoctoral Fellowship of Sichuan University (2020SCU12060), “One Thousand Talents” program from the Chinese Central Government and Sichuan Province, the Fundamental Research Funds for the Central Universities (SCU2019D013) and the National Natural Science Foundation of China (82002650).

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