Expression of nuclear receptor co­activator 7 protein is associated with poor prognosis of breast cancer.

Nuclear receptor coactivator 7 (NCOA7) is an estrogen receptor binding protein. Its role in breast cancer progression has so far remained elusive. The present study aimed to determine the expression levels of NCOA7 in breast tumor samples and confirmed its potential utility as a breast cancer prognostic biomarker. The expression of NCOA7 was detected by immunohistochemical staining in 241 breast cancer tumor samples and 163 adjacent normal tissue samples. The association of NCOA7 expression with the clinicopathological characteristics and overall survival were statistically analyzed. Cell proliferation was determined by Cell Counting Kit-8 and colony-formation assays. Cell migration was detected using wound-healing and Transwell assays. NCOA7 was positively expressed in 44% of breast tumor tissues. The expression of NCOA7 was positively associated with tumor size (T-stage; P=0.005) and lymph node metastasis (N-stage; P=0.008). Additional statistical analysis indicated that the expression of NCOA7 was associated with patient age, tumor size and lymph node metastasis in patients with triple-negative breast cancer (TNBC) compared with that in patients with non-TNBC. The overall survival of patients with NCOA7-positive breast cancer was significantly lower than that of patients with NCOA7-negative breast cancer (P=0.006). Among the patients with lymph node metastasis, the overall survival was reversely associated with the expression of NCOA7 (P=0.042). Furthermore, knockdown of NCOA7 expression in breast cancer T47D and MCF7 cells significantly inhibited both cell proliferation and migration, suggesting that this protein may exert a role in driving breast cancer progression. Taken together, these results indicate that the expression of NCOA7 is associated with poor prognosis of breast cancer and suggest that this protein may be a driver for metastasis and a potential therapeutic target for advanced breast cancer.

Macrophages-derived exo-miR-4449 induced by Cryptococcus affects HUVEC permeability and promotes pyroptosis in BEAS-2B via the HIC1 pathway.

Macrophages have recently been discovered to assume a significant role in the progression of cryptococcosis. However, the potential involvement of macrophage-derived exosomes in the pathogenesis of cryptococcosis remains uncertain. In this study, we investigated the changes of microRNAs in macrophage exosomes (exo-miRNAs) in cryptococcal infections and the role of markedly altered exo-miRNAs in the modulation of Human Umbilical Vein Endothelial Cells (HUVEC) permeability and ROS accumulation and pyroptosis in Human Bronchial Epithelioid Cells (BEAS-2B). Techniques such as microarray analysis and real-time quantitative PCR were used to detect different exo-miRNAs and to screen for the most highly expressed exo-miRNAs. Then its mimics were transfected into HUVEC to study its effect on the monolayer permeability of HUVEC. Finally, the relationship between this exo-miRNAs and the ROS accumulation and pyroptosis was verified by bioinformatics analysis. The results showed that five exo-miRNAs were overexpressed and two exo-miRNAs were reduced, among which, exo-miR-4449 was expressed at the highest level. Exo-miR-4449 could be internalized by HUVEC and enhanced its monolayer permeability. Moreover, exo-miR-4449 was found to promote ROS accumulation and pyroptosis in BEAS-2B through HIC1 pathway. Thus, exo-miR-4449 plays an important role in the pathogenesis of cryptococcosis and holds promise as a significant biomarker for treatment.

Umbilical cord mesenchymal stem cells inhibited inflammation of bronchial epithelial cells by regulating Hedgehog pathway.

This study aimed to explore the role and mechanism of umbilical cord mesenchymal stem cells (UCMSCs) in regulating inflammation of bronchial epithelial cells. Transforming growth factor beta-1 (TGF-ß1) was used to induce inflammation in human bronchial epithelial cells. Cell proliferation was detected through CCK8 and cell apoptosis was detected by Annexin V and propidium iodide double staining. E-cadherin and α-smooth muscle actin (α-SMA) were detected by immunofluorescence, and tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in culture medium supernatant were detected by ELISA. The expression of E-cadherin, α-SMA, Sonic hedgehog (Shh), Gli1 and Snail was detected by Western blot analysis. Compared with the control group, bronchial epithelial cells treated with TGF-ß1 showed significantly decreased proliferation, increased apoptosis, increased secretion of TNF-α and IL-6, increased expression of α-SMA, Shh, Gli1 and Snail and decreased E-cadherin expression. However, co-culture with UCMSCs inhibited TGF-ß1-induced changes in human bronchial epithelial cell proliferation, apoptosis, secretion of TNF-α and IL-6 and activation of the Hedgehog pathway. In conclusion, UCMSCs have protective effects on TGF-ß1-induced inflammation in human bronchial epithelial cells by regulating the Hedgehog pathway.

Alpha-1 antitrypsin inhibits fractalkine-mediated monocyte-lung endothelial cell interactions.

Chronic obstructive pulmonary disease (COPD) is characterized by nonresolving inflammation fueled by breach in the endothelial barrier and leukocyte recruitment into the airspaces. Among the ligand-receptor axes that control leukocyte recruitment, the full-length fractalkine ligand (CX3CL1)-receptor (CX3CR1) ensures homeostatic endothelial-leukocyte interactions. Cigarette smoke (CS) exposure and respiratory pathogens increase expression of endothelial sheddases, such as a-disintegrin-and-metalloproteinase-domain 17 (ADAM17, TACE), inhibited by the anti-protease α-1 antitrypsin (AAT). In the systemic endothelium, TACE cleaves CX3CL1 to release soluble CX3CL1 (sCX3CL1). During CS exposure, it is not known whether AAT inhibits sCX3CL1 shedding and CX3CR1+ leukocyte transendothelial migration across lung microvasculature. We investigated the mechanism of sCX3CL1 shedding, its role in endothelial-monocyte interactions, and AAT effect on these interactions during acute inflammation. We used two, CS and lipopolysaccharide (LPS) models of acute inflammation in transgenic Cx3cr1gfp/gfp mice and primary human endothelial cells and monocytes to study sCX3CL1-mediated CX3CR1+ monocyte adhesion and migration. We measured sCX3CL1 levels in plasma and bronchoalveolar lavage (BALF) of individuals with COPD. Both sCX3CL1 shedding and CX3CR1+ monocytes transendothelial migration were triggered by LPS and CS exposure in mice, and were significantly attenuated by AAT. The inhibition of monocyte-endothelial adhesion and migration by AAT was TACE-dependent. Compared with healthy controls, sCX3CL1 levels were increased in plasma and BALF of individuals with COPD, and were associated with clinical parameters of emphysema. Our results indicate that inhibition of sCX3CL1 as well as AAT augmentation may be effective approaches to decrease excessive monocyte lung recruitment during acute and chronic inflammatory states.NEW & NOTEWORTHY Our novel findings that AAT and other inhibitors of TACE, the sheddase that controls full-length fractalkine (CX3CL1) endothelial expression, may provide fine-tuning of the CX3CL1-CX3CR1 axis specifically involved in endothelial-monocyte cross talk and leukocyte recruitment to the alveolar space, suggests that AAT and inhibitors of sCX3CL1 signaling may be harnessed to reduce lung inflammation.

NEDD4 E3 ubiquitin ligases: Promising biomarkers and therapeutic targets for cancer.

Accumulating evidence has demonstrated that NEDD4 E3 ubiquitin ligase family plays a pivotal oncogenic role in a variety of malignancies via mediating ubiquitin dependent degradation processes. Moreover, aberrant expression of NEDD4 E3 ubiquitin ligases is often indicative of cancer progression and correlated with poor prognosis. In this review, we are going to address association of expression of NEDD4 E3 ubiquitin ligases with cancers, the signaling pathways and the molecular mechanisms by which the NEDD4 E3 ubiquitin ligases regulate oncogenesis and progression, and the therapies targeting the NEDD4 E3 ubiquitin ligases. This review provides the systematic and comprehensive summary of the latest research status of E3 ubiquitin ligases in the NEDD4 subfamily, and proposes that NEDD4 family E3 ubiquitin ligases are promising anti-cancer drug targets, aiming to provide research direction for clinical targeting of NEDD4 E3 ubiquitin ligase therapy.

Structure, activity and function of the lysine methyltransferase SETD5.

SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by methylating histone H3 on lysine 36 (H3K36). These well-characterized functions of SETD5 are transcription regulation, euchromatin formation, and RNA elongation and splicing. SETD5 is frequently mutated and hyperactive in both human neurodevelopmental disorders and cancer, and could be down-regulated by degradation through the ubiquitin-proteasome pathway, but the biochemical mechanisms underlying such dysregulation are rarely understood. Herein, we provide an update on the particularities of SETD5 enzymatic activity and substrate specificity concerning its biological importance, as well as its molecular and cellular impact on normal physiology and disease, with potential therapeutic options.

Non-hippo kinases: indispensable roles in YAP/TAZ signaling and implications in cancer therapy.

The transcriptional co-activators Yes-associated protein (YAP) and PDZ-binding domain (TAZ) are the known downstream effectors of the Hippo kinase cascade. YAP/TAZ have been shown to play important roles in cellular growth and differentiation, tissue development and carcinogenesis. Recent studies have found that, in addition to the Hippo kinase cascade, multiple non-Hippo kinases also regulate the YAP/TAZ cellular signaling and produce important effects on cellular functions, particularly on tumorigenesis and progression. In this article, we will review the multifaceted regulation of the YAP/TAZ signaling by the non-Hippo kinases and discuss the potential application of the non-Hippo kinase-regulated YAP/TAZ signaling for cancer therapy.

Adoptive immune transfer from donors offers Anti-HBV protection to HBsAb-negative patients after Allo-HSCT.

Adoptive transfer of hepatitis B virus (HBV) immunity may occur following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we investigated the adoptive transfer of HBV immunity in 112 patients without HBV surface antibody (HBsAb) (HBsAb-) at the time of their first allo-HSCT. After allo-HSCT, HBV-DNA（87.5%） and HBsAg（11.1%%）cleared in HBsAg+ patients. All HBsAg- patients acquired HBsAb immediately. Nevertheless, HBsAb titers subsequently declined, and 39/67 (58.2%) patients lost HBsAb during follow-up. The 5-year overall survival (OS) was better in patients who lost HBsAb. Multivariate analysis showed that the independent risk factors for OS were lack of cytomegalovirus (CMV) clearance, acute graft-versus-host disease (aGVHD), and no HBsAb loss. Overall, adoptive immune transfer offers anti-HBV protection to patients without HBsAb, as they acquire HBsAb and clear HBV-DNA and HBsAg, while HBsAb loss after allo-HSCT predicts better survival.

Characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for immune checkpoint inhibitor-related pneumonitis.

As immune checkpoint inhibitors (ICIs) are widely used, a series of immune-related adverse events (irAEs) have been reported, including immune checkpoint inhibitor-related pneumonitis (ICI-pneumonitis). The incidence of ICI-pneumonitis is higher in reality than in clinical trials. The diagnosis is challenging, mainly based on clinical and imaging features, and requires the exclusion of other causes. The data on the biological mechanisms of ICI-pneumonitis are scarce, resulting in little knowledge of the best treatment for ICI-pneumonitis. Bronchoalveolar lavage (BAL) may be helpful to identify the biological differences or find predictive biomarkers, and may in turn help to develop phenotype-specific targeted drugs to treat ICI-pneumonitis. Herein, we outline the characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for ICI-pneumonitis. Through careful sorting and literature review, we find crosstalk between pathogenic Th17/Th1 cells (i.e., Th17.1) and pro-inflammatory monocytes, and activation of Th17(/Th1)/IL-17A (/IFN-γ) pathways may play a key role in the pathogenesis of ICI-pneumonitis. Disruption of the interaction between pathogenic Th17/Th1 cells and pro-inflammatory monocytes (such as, anti-IL-23) may be a potential treatment for ICI-pneumonitis. We first describe the possible pathophysiological mechanisms of ICI-pneumonitis, hoping to contribute to the optimization of diagnosis and treatment, as well as provide readers with research inspiration.

Activation of E3 ubiquitin ligase WWP2 by non-receptor tyrosine kinase ACK1.

WW domain containing E3 ubiquitin protein ligase 2 (WWP2) is a member of the NEDD4 E3 ubiquitin ligase family. WWP2 ligase activity is regulated by the 2, 3-linker auto-inhibition. Tyrosine phosphorylation of the 2, 3-linker was identified as an activating means for releasing the auto-inhibition of WWP2. However, the tyrosine kinase (TK) for the phosphorylation and activation remains unknown. In this report, we have found that non-receptor TK ACK1 binds to the WW3 domain of WWP2 and phosphorylates WWP2. ACK1 phosphorylates WWP2 at the 2, 3-linker and partially activates the ubiquitination ligase activity. Unexpectedly, tyrosine phosphorylation of the 2, 3-linker seems not a major mode for activation of WWP2, as ACK1 causes much higher activation of the 2, 3-linker tyrosine phosphorylation defective mutants of WWP2 than that of wild-type WWP2. Furthermore, epidermal growth factor (EGF) stimulates tyrosine phosphorylation of WWP2 and this EGF-stimulated phosphorylation of WWP2 is mediated by ACK1. Finally, knockdown of WWP2 by shWWP2 inhibits the EGF-dependent cell proliferation of lung cancer A549 cells, suggesting that WWP2 may function in the EGFR signaling in lung cancer progression. Taken together, our findings have revealed a novel mechanism underlying activation of WWP2.

The Role of HECT E3 Ubiquitin Ligases in Colorectal Cancer.

Colorectal cancer (CRC) is estimated to rank as the second reason for cancer-related deaths, and the prognosis of CRC patients remains unsatisfactory. Numerous studies on gastrointestinal cell biology have shown that the E3 ligase-mediated ubiquitination exerts key functions in the pathogenesis of CRC. The homologous to E6-associated protein C-terminus (HECT) family E3 ligases are a major group of E3 enzymes, featured with the presence of a catalytic HECT domain, which participate in multiple cellular processes; thus, alterations in HECT E3 ligases in function or expression are closely related to the occurrence and development of many human malignancies, including-but not limited to-CRC. In this review, we summarize the potential role of HECT E3 ligases in colorectal carcinogenesis and the related underlying molecular mechanism to expand our understanding of their pathological functions. Exploiting specific inhibitors targeting HECT E3 ligases could be a potential therapeutic strategy for CRC therapy in the future.

Emerging roles of the HECT E3 ubiquitin ligases in gastric cancer.

Gastric cancer (GC) is one of the most pernicious gastrointestinal tumors with extraordinarily high incidence and mortality. Ubiquitination modification of cellular signaling proteins has been shown to play important roles in GC tumorigenesis, progression, and prognosis. The E3 ubiquitin ligase is the crucial enzyme in the ubiquitination reaction and determines the specificity of ubiquitination substrates, and thus, the cellular effects. The HECT E3 ligases are the second largest E3 ubiquitin ligase family characterized by containing a HECT domain that has E3 ubiquitin ligase activity. The HECT E3 ubiquitin ligases have been found to engage in GC progression. However, whether HECT E3 ligases function as tumor promoters or tumor suppressors in GC remains controversial. In this review, we will focus on recent discoveries about the role of the HECT E3 ubiquitin ligases, especially members of the NEDD4 and other HECT E3 ligase subfamilies, in GC.

Hydrogen-rich water alleviates chilling injury-induced lignification of kiwifruit by inhibiting peroxidase activity and improving antioxidant system.

BACKGROUND: Kiwifruit is prone to chilling stress and displays chilling injury (CI) such as lignification; however, the underlying physicochemical mechanism remains largely unknown. Here, the changes in levels of quality attributes, lignin biosynthesis, antioxidant system and sugars were compared in kiwifruit between control and hydrogen-rich water (HRW) treatments during cold storage for 90 days at 0 °C. RESULTS: The results reveal that HRW is an effective measure for CI alleviation, as indicated by the decrease in lignification level with repressed peroxidase activity but enhanced polyphenol oxidase activity. The amelioration of membrane peroxidation was suggested by the repressed levels of H2 O2 and malondialdehyde. They were accompanied by the improvement of antioxidant system, which is supported by the enhancement of sugars including fructose and glucose. CONCLUSION: In conclusion, HRW can enhance chilling tolerance, as suggested by the alleviation of lignification through inhibiting peroxidase activity and elevating the antioxidant system to attenuate membrane peroxidation. © 2022 Society of Chemical Industry.

ETS1 is a prognostic biomarker of triple-negative breast cancer and promotes the triple-negative breast cancer progression through the YAP signaling.

E26 transcription factor-1 (ETS1) is involved in extracellular matrix remodeling, migratory infiltration and angiogenesis in tumors and known to play an important role in tumor progression. However, the mechanism by which ETS1 promotes tumor progression remains elusive. In this report, we show that ETS1 is highly expressed in breast tumor tissues and specifically associated with the tumor metastasis and poor survival in triple negative breast cancer (TNBC) tumors, upon analysis by immunohistochemical (IHC) staining of tumor samples from 240 breast cancer cases. Depletion of ETS1 in TNBC cells by shETS1 significantly inhibited the cell proliferation and migration. Mechanistically, knockdown of ETS1 in TNBC cells dramatically reduced expression of YAP and the YAP target genes, and overexpression of YAP in the ETS1 knockdown cells restored the cell proliferation and migration. These data indicate that YAP is a downstream effector mediating the ETS1-promoted TNBC cell proliferation and migration. Taken together, our results suggest that ETS1 promotes TNBC progression through the YAP signaling.

Overexpression of SCYL1 Is Associated with Progression of Breast Cancer.

SCYL1 is a pseudokinase and plays roles in cell division and gene transcription, nuclear/cytoplasmic shuttling of tRNA, protein glycosylation, and Golgi morphology. However, the role of SCYL1 in human breast cancer progression remains largely unknown. In this study, we determined expression of SCYL1 in breast cancer by searching the Cancer Genome Atlas (TCGA) and Tumor Immunoassay Resource (TIMER) databases. Meanwhile, we collected breast tumor tissue samples from 247 cases and detected expression of SCYL1 in the tumors using the tissue microarray assay (TMA). Association of SCYL1 with prognosis of breast cancer was determined based on the PrognoScan database. The results have shown that SCYL1 is overexpressed in breast cancer, and the expression of SCYL1 is associated with poor clinical outcomes of breast cancer patients. Furthermore, knockdown of SCYL1 by shRNAs significantly inhibited the proliferation and migration of breast cancer cells. Taken together, our data suggest that SCYL1 is a biomarker for poor prognosis of breast cancer, has a promoting role in breast cancer progression, and is a potential target for breast cancer therapy.

Abscisic acid alleviates chilling injury in cold-stored peach fruit by regulating ethylene and hydrogen peroxide metabolism.

Peach (Prunus persica (L.) Batsch) is susceptible to chilling injury under improper low-temperature storage (2°C-5°C). Previous research has shown that abscisic acid (ABA) alleviates chilling injury in fruits and vegetables, but the potential mechanism is still unclear. To explore its effectiveness and potential mechanism in alleviating chilling injury during cold storage, exogenous ABA was applied to peach fruit by immersion in 100 µmol L-1 solutions for 10 min. In our experiment, ABA alleviated chilling injury by reducing hydrogen peroxide (H2O2) content and ethylene production. In addition, ABA inhibited the expression of the ethylene synthesis-related genes PpACO1 and PpEIN2. At the same time, ABA activated the antioxidant enzymatic pathway and the ascorbate-glutathione (AsA-GSH) cycle, the transcript abundance encoding genes related to antioxidant enzyme activities also changed correspondingly. The results suggested that ABA alleviated chilling injury by scavenging excessive H2O2 by promoting antioxidant enzymes and the AsA-GSH pathway.

Nutraceuticals for the Treatment of IBD: Current Progress and Future Directions.

Inflammatory bowel disease (IBD) is a chronic relapsing-remitting inflammatory disease of the gastrointestinal tract. Patients are usually diagnosed in adolescence and early adulthood and need lifelong treatment. In recent years, it has been found that diet plays an important role in the pathogenesis of IBD. Diet can change intestinal barrier function, affect the structure and function of intestinal flora, and promote immune disorder, thus promoting inflammation. Many patients believe that diet plays a role in the onset and treatment of the disease and changes their diet spontaneously. This review provides some insights into how nutraceuticals regulate intestinal immune homeostasis and improve intestinal barrier function. We reviewed the research results of dietary fiber, polyphenols, bioactive peptides, and other nutraceuticals in the prevention and treatment of IBD and sought better alternative or supplementary treatment methods for IBD patients.

Phytic Acid Treatment Inhibits Browning and Lignification to Promote the Quality of Fresh-Cut Apples during Storage.

Browning and lignification often occur in fresh-cut apple processing, leading to quality deterioration and limiting the shelf life of products. In this study, 0.8% (v/v) phytic acid was used to improve the quality and shelf life of fresh-cut apples. From the results, the browning was inhibited by the phytic acid treatment and the browning index (BI) of the control fruit was 1.62 times that of phytic acid treatment at 2 d of storage. The lignin content in phytic acid-treated fruit significantly decreased at 2, 4, and 6 d of storage compared to the control. Phytic acid treatment also reduced H2O2 and malonaldehyde (MDA) contents, which may indicate lighter membrane damage to apples. Compared with the control, the polyphenol oxidase (PPO) and peroxidase (POD) activities decreased while superoxide dismutase (SOD) and catalase (CAT) activities increased in phytic acid-treated fruit. Consistent with the lignin content, the activities of phenylpropane metabolism-related enzymes phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H), and 4-coumarate: CoA ligase (4CL) were inhibited by phytic acid treatment. In conclusion, phytic acid alleviated the browning and lignification of fresh-cut apples by reducing PPO and POD activities, maintaining cell membrane integrity, and inhibiting phenylpropane metabolism.

Estrogen Receptor Bio-Activities Determine Clinical Endocrine Treatment Options in Estrogen Receptor-Positive Breast Cancer.

In estrogen receptor positive (ER+) breast cancer therapy, estrogen receptors (ERs) are the major targeting molecules. ER-targeted therapy has provided clinical benefits for approximately 70% of all breast cancer patients through targeting the ERα subtype. In recent years, mechanisms underlying breast cancer occurrence and progression have been extensively studied and largely clarified. The PI3K/AKT/mTOR pathway, microRNA regulation, and other ER downstream signaling pathways are found to be the effective therapeutic targets in ER+ BC therapy. A number of the ER+ (ER+) breast cancer biomarkers have been established for diagnosis and prognosis. The ESR1 gene mutations that lead to endocrine therapy resistance in ER+ breast cancer had been identified. Mutations in the ligand-binding domain of ERα which encoded by ESR1 gene occur in most cases. The targeted drugs combined with endocrine therapy have been developed to improve the therapeutic efficacy of ER+ breast cancer, particularly the endocrine therapy resistance ER+ breast cancer. The combination therapy has been demonstrated to be superior to monotherapy in overall clinical evaluation. In this review, we focus on recent progress in studies on ERs and related clinical applications for targeted therapy and provide a perspective view for therapy of ER+ breast cancer.

Geranylgeranylation signaling promotes breast cancer cell mitosis via the YAP-activated transcription of kinetochore/centromere genes.

Geranylgeranylation signaling plays an important role in cancer cell proliferation. Our previous studies have shown that the YAP is one of the geranylgeranylation signal transducers in breast cancer cells (Mi W, et al., Oncogene. 2015; 34(24): 3095-3106). However, the downstream effectors that mediate the promoting effect of the geranylgeranylation/YAP signal axis on breast cancer cell proliferation remain elusive. In this report, we investigated the pathway that mediates the effect of the geranylgeranylation on breast cancer cell proliferation. The results have shown that inhibition of geranylgeranyl biosynthesis inactivates transcription of a set of kinetochore/centromere genes. Further biochemical and cell biological studies demonstrated that inhibition of geranylgeranyl biosynthesis significantly reduced the level of key kinetochore/centromere proteins, thus caused a defect in mitosis. Knockdown of YAP caused similar inhibitory effects on the kinetochore/centromere gene expression and mitosis to that of inhibition of geranylgeranyl biosynthesis. Furthermore, we found that E2F1, the gene coding for E2F1 that is known to activate expression of cell cycle genes, is a target gene of YAP. Knockdown of E2F1 also reduced expression of the kinetochore/centromere genes, suggesting that the activation effect of YAP on expression of the kinetochore/centromere genes may be mediated by E2F1. Our studies have proposed a novel geranylgeranylation-dependent cancer cell proliferation signaling pathway in which geranylgeranylation signaling promotes cancer cell mitosis via the YAP-activated transcription of kinetochore/centromere genes.