Emerging role of lncRNAs as mechanical signaling molecules in mechanotransduction and their association with Hippo-YAP signaling:a review

Cells within tissues are subject to various mechanical forces,including hydrostatic pressure,shear stress,compression,and tension.These mechanical stimuli can be converted into biochemical signals through mechanoreceptors or cytoskeleton-dependent response processes,shaping the microenvironment and maintaining cellular physiological balance.Several studies have demonstrated the roles of Yes-associated protein(YAP)and its homolog transcriptional coactivator with PDZ-binding motif(TAZ)as mechanotransducers,exerting dynamic influence on cellular phenotypes including differentiation and disease pathogenesis.This regulatory function entails the involvement of the cytoskeleton,nucleoskeleton,integrin,focal adhesions(FAs),and the integration of multiple signaling pathways,including extracellular signal-regulated kinase(ERK),wingless/integrated(WNT),and Hippo signaling.Furthermore,emerging evidence substantiates the implication of long non-coding RNAs(lncRNAs)as mechanosensitive molecules in cellular mechanotransduction.In this review,we discuss the mechanisms through which YAP/TAZ and lncRNAs serve as effectors in responding to mechanical stimuli.Additionally,we summarize and elaborate on the crucial signal molecules involved in mechanotransduction.

LncFASA promotes cancer ferroptosis via modulating PRDX1 phase separation

Ferroptosis, a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation, has a potential physiological function in tumor suppression, but its underlying mechanisms have not been fully elucidated. Here, we report that the long non-coding RNA(lncRNA) LncFASA increases the susceptibility of triple-negative breast cancer(TNBC) to ferroptosis. As a tumor suppressor, LncFASA drives the formation of droplets containing peroxiredoxin1(PRDX1), a member of the peroxidase family, resulting in the accumulation of lipid peroxidation via the SLC7A11-GPX4 axis. Mechanistically, LncFASA directly binds to the Ahpc-TSA domain of PRDX1, inhibiting its peroxidase activity by driving liquid-liquid phase separation, which disrupts intracellular ROS homeostasis. Notably, high LncFASA expression indicates favorable overall survival in individuals with breast cancer, and LncFASA impairs the growth of breast xenograft tumors by modulating ferroptosis. Together, our findings illustrate the crucial role of this lncRNA in ferroptosis-mediated cancer development and provide new insights into therapeutic strategies for breast cancer.

AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization

Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair cell function.ANSD represents up to 15%of individuals with hearing impairments.Through mutation screening,bioinformatic analysis and expression studies,we have previously identified several apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants in ANSD families and in some other sporadic cases.Here,to elucidate the pathogenic mechanisms underlying each AIFM1 variant,we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system and constructed AIF-wild type(WT)and AIF-mutant(mut)(p.T260A,p.R422W,and p.R451Q)stable transfection cell lines.We then analyzed AIF structure,coenzyme-binding affinity,apoptosis,and other aspects.Results revealed that these variants resulted in impaired dimerization,compromising AIF function.The reduction reaction of AIF variants had proceeded slower than that of AIF-WT.The average levels of AIF dimerization in AIF variant cells were only 34.5%-49.7%of that of AIF-WT cells,resulting in caspase-independent apoptosis.The average percentage of apoptotic cells in the variants was 12.3%-17.9%,which was significantly higher than that(6.9%-7.4%)in controls.However,nicotinamide adenine dinucleotide(NADH)treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells.Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD,and introduce NADH as a potential drug for ANSD treatment.Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.

Tumor immune checkpoints and their associated inhibitors

Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.

Iron metabolism,ferroptosis,and lncRNA in cancer: knowns and unknowns

Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation.As an essential trace element,iron is vital for many biological processes.Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation.Ferroptosis,a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids(PUFAs),is a promising therapeutic target for therapyresistant cancers.Previous studies have reported that long noncoding RNA(lncRNA)is a group of critical regulators involved in modulating cell metabolism,proliferation,apoptosis,and ferroptosis.In this review,we summarize the associations among iron metabolism,ferroptosis,and ferroptosis-related lncRNA in tumorigenesis.This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.

YB1 regulates miR-205/200b-ZEB1 axis by inhibiting microRNA maturation in hepatocellular carcinoma

Background:Y-box binding protein 1(YB1 or YBX1)plays a critical role in tumorigenesis and cancer progression.However,whether YB1 affects malignant transformation by modulating non-codingRNAs remains largely unknown.This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network.Methods:The biological functions of YB1 in hepatocellular carcinoma(HCC)cells were investigated by cell proliferation,wound healing,and transwell invasion assays.The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines.The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR,dual-luciferase reporter assay,RNA immunoprecipitation,and pull-down assay.The relationships of YB1,DGCR8,Dicer,TUT4,and TUT1 were identified by pull-down and coimmunoprecipitation experiments.The cellular co-localization of YB1,DGCR8,and Dicer were detected by immunofluorescent staining.The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice.The expression levels of epithelial tomesenchymal transition markerswere detected by immunoblotting and immunohistochemistry assays.Results:YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b‒ZEB1 axis partially in a Snail-independent manner.YB1 suppressedmiR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain.Subsequently,the downregulation of miR-205 and miR-200b enhanced ZEB1 expression,thus leading to increased cell migration and invasion.Furthermore,statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis.Conclusion:This study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR-205/200b‒ZEB1 axis in HCC cells.Furthermore,these results highlight that YB1 may play biological functions via miRNAs-mediated gene regulation,and it can serve as a potential therapeutic target in human cancers.

Cancer immunotherapy: an evolving paradigm

The inhibition of the host’s natural immune response by tumor cells was widely reported in the early phases of the development of oncology therapy,and the concept of employing the host’s immune system to treat cancer,i.e.tumor immunotherapy,is not new.However,as a result of early theoretical constraints,clinical application of immunotherapy did not go smoothly and lagged significantly behind radiation and chemotherapy.The path has been winding,but the future now seems promising.Immunotherapy research has advanced enormously as a result of the maturing of immuno-editing theory and the creation of numerous technologies,despite a number of unsuccessful endeavors and clinical studies.Since around 1998,the US Food and Drug Administration(FDA)has approved a variety of tumor immunotherapies,including cytokines(interleukin-2,interferons),cancer vaccines(Provenge),immune checkpoint inhibitors(ipilimumab),and cellular therapies(chimeric antigen receptor-T(CAR-T)),signaling a boom in the field.