RNA binding proteins: Linking mechanotransduction and tumor metastasis
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).
References (145)
- et al.
Control of mechanotransduction by molecular clutch dynamics
Trends Cell Biol.
(2018) Mechanotransduction in development
Curr. Top. Dev. Biol.
(2011)- et al.
Systemic spread is an early step in breast cancer
Canc. Cell
(2008) - et al.
Forcing through tumor metastasis: the interplay between tissue rigidity and epithelial-mesenchymal transition
Trends Cell Biol.
(2016) - et al.
Mechanotransduction activates alpha(5)beta(1) integrin and PI3K/Akt signaling pathways in mandibular osteoblasts
Exp. Cell Res.
(2011) - et al.
Crosstalk between caveolin-1/extracellular signal-regulated kinase (ERK) and beta-catenin survival pathways in osteocyte mechanotransduction
J. Biol. Chem.
(2013) - et al.
Mechanotransduction in cancer
Curr. Opin. Chem. Eng.
(2016) - et al.
Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization
Cell
(2015) - et al.
Integrins in mechanotransduction
Curr. Opin. Cell Biol.
(2013) - et al.
Control of motile and invasive cell phenotypes by focal adhesion kinase
Biochim. Biophys. Acta
(2004)
Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer
Cell
YAP/TAZ at the roots of cancer
Canc. Cell
Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its Co-activation of bax transcription
J. Biol. Chem.
Heterogeneous ribonucleoprotein F regulates YAP expression via a G-tract in 3'UTR
Biochim. Biophys. Acta Gene Regul. Mech.
LINC01413/hnRNP-K/ZEB1 Axis Accelerates cell proliferation and EMT in colorectal cancer via inducing YAP1/TAZ1 translocation
Mol. Ther. Nucleic Acids
Integrin α6β4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100a4/metastasin
J. Biol. Chem.
hnRNP L regulates differences in expression of mouse integrin alpha2beta1
Blood
CNOT7/hCAF1 is involved in ICAM-1 and IL-8 regulation by tristetraprolin
Cell. Signal.
S-nitrosylation of heterogeneous nuclear ribonucleoprotein A/B regulates osteopontin transcription in endotoxin-stimulated murine macrophages
J. Biol. Chem.
Control of immune cell homeostasis and function by lncRNAs
Trends Immunol.
Selectins promote tumor metastasis
Semin. Canc. Biol.
Identification of novel isoforms of mouse L-selectin with different carboxyl-terminal tails
J. Biol. Chem.
Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44
J. Biol. Chem.
Circulating soluble P-selectin must dimerize to promote inflammation and coagulation in mice
Blood
Alternatively spliced isoform of P-selectin is present in vivo as a soluble molecule
J. Biol. Chem.
CD44/CD44v6 a reliable companion in cancer-initiating cell maintenance and tumor progression
Front Cell Dev. Biol.
Direct regulation of alternative splicing by SMAD3 through PCBP1 is essential to the tumor-promoting role of TGF-beta
Mol. Cell
Mechanical control of morphogenesis by Fat/Dachsous/Four-jointed planar cell polarity pathway
Science
The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis
Development
Mechanotransduction gone awry
Nat. Rev. Mol. Cell Biol.
Epithelial mesenchymal transition in tumor metastasis
Annu. Rev. Pathol.
Role of YAP/TAZ in mechanotransduction
Nature
Review of cellular mechanotransduction
J. Phys. D Appl. Phys.
Aberrant RNA splicing in cancer
Annu. Rev. Cell Biol.
Context-dependent control of alternative splicing by RNA-binding proteins
Nat. Rev. Genet.
RNA splicing factors as oncoproteins and tumour suppressors
Nat. Rev. Canc.
Gene regulation in the immune system by long noncoding RNAs
Nat. Immunol.
Cellular functions of long noncoding RNAs
Nat. Cell Biol.
Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation
Mol. Cell
Nuclear innate sensors for nucleic acids in immunity and inflammation
Immunol. Rev.
Focal adhesion kinase: in command and control of cell motility
Nat. Rev. Mol. Cell Biol.
Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape
J. Immunother. Canc.
YAP/TAZ upstream signals and downstream responses
Nat. Cell Biol.
Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration
Sci. Signal.
Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth
Nat. Cell Biol.
YAP regulates cell mechanics by controlling focal adhesion assembly
Nat. Commun.
PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis
Nat. Commun.
The biology of YAP/TAZ: hippo signaling and beyond
Physiol. Rev.
The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease
Development
Role of YAP/TAZ in mechanotransduction
Nature
Cited by (12)
Expanding the horizons of targeted protein degradation: A non-small molecule perspective
2024, Acta Pharmaceutica Sinica BIGF2BP3 enhances lipid metabolism in cervical cancer by upregulating the expression of SCD
2024, Cell Death and DiseaseThe Emerging Roles of LIS1 Biomechanics in Cellular and Cortical Homeostasis
2023, Neocortical Neurogenesis in Development and EvolutionThe RNA-binding protein GRSF1 promotes hepatocarcinogenesis via competitively binding to YY1 mRNA with miR-30e-5p
2022, Journal of Experimental and Clinical Cancer Research