SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1.

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 (MKRN1) and promoting the expression of the dominant and oncogenic isoform, MKRN1-T1. Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.

Same allocation proposed by an individual or a group elicits distinct responses: Evidence from event-related potentials and neural oscillation.

People tend to perceive the same information differently depending on whether it is expressed in an individual or a group frame. It has also been found that the individual (vs. group) frame of expression tends to lead to more charitable giving and greater tolerance of wealth inequality. However, little is known about whether the same resource allocation in social interactions elicits distinct responses depending on proposer type. Using the second-party punishment task, this study examined whether the same allocation from different proposers (individual vs. group) leads to differences in recipient behavior and the neural mechanisms. Behavioral results showed that reaction times were longer in the unfair (vs. fair) condition, and this difference was more pronounced when the proposer was the individual (vs. group). Neural results showed that proposer type (individual vs. group) influenced early automatic processing (indicated by AN1, P2, and central alpha band), middle processing (indicated by MFN and right frontal theta band), and late elaborative processing (indicated by P3 and parietal alpha band) of fairness in resource allocation. These results revealed more attentional resources were captured by the group proposer in the early stage of fairness processing, and more cognitive resources were consumed by processing group-proposed unfair allocations in the late stage, possibly because group proposers are less identifiable than individual proposers. The findings provide behavioral and neural evidence for the effects of "individual/group" framing leading to cognitive differences. They also deliver insights into social governance issues, such as punishing individual and/or group violations.

Spermatid perinuclear RNA-binding protein promotes UBR5-mediated proteolysis of Dicer to accelerate triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with no targeted therapy. Spermatid perinuclear RNA binding protein (STRBP), a poorly characterized RNA-binding protein (RBP), has an essential role in normal spermatogenesis and sperm function, but whether and how its dysregulation contributing to cancer progression has not yet been explored. Here, we report that STRBP functions as a novel oncogene to drive TNBC progression. STRBP expression was upregulated in TNBC tissues and correlated with poor disease prognosis. Functionally, STRBP promoted TNBC cell proliferation, migration, and invasion in vitro, and enhanced xenograft tumor growth and lung colonization in mice. Mechanistically, STRBP interacted with Dicer, a core component of the microRNA biogenesis machinery, and promoted its proteasomal degradation through enhancing its interaction with E3 ubiquitin ligase UBR5. MicroRNA-sequencing analysis identified miR-200a-3p as a downstream effector of STRBP, which was regulated by Dicer and affected epithelial-mesenchymal transition. Importantly, the impaired malignant phenotypes of TNBC cells caused by STRBP depletion were largely rescued by knockdown of Dicer, and these effects were compromised by transfection of miR-200a-3p mimics. Collectively, these findings revealed a previously unrecognized oncogenic role of STRBP in TNBC progression and identified STRBP as a promising target against TNBC.

C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) presents the most challenging subtype of all breast cancers because of its aggressive clinical phenotypes and absence of viable therapy targets. In order to identify effective molecular targets for treating patients with TNBC, we conducted an integration analysis of our recently published TNBC dataset of quantitative proteomics and RNA-Sequencing, and found the abnormal upregulation of chromosome 9 open reading frame 142 (C9orf142) in TNBC. However, the functional roles of C9orf142 in TNBC are unclear. METHODS: In vitro and in vivo functional experiments were performed to assess potential roles of C9orf142 in TNBC. Immunoblotting, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescent staining were used to investigate the expression levels of C9orf142 and its downstream molecules. The molecular mechanisms underlying C9orf142-regulated mouse double minute 2 (MDM2)-binding protein (MTBP) were determined by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. RESULTS: In TNBC tissues and metastatic lymph nodes, we observed that C9orf142 exhibited abnormal up-regulation, and its elevated expression was indicative of unfavorable prognosis for TNBC patients. Both in vitro and in vivo functional experiments demonstrated that C9orf142 accelerated TNBC growth and metastasis. Further mechanism exploration revealed that C9orf142 transcriptionally activated MTBP, thereby regulating its downstream MDM2/p53/p21 signaling axis and the transition of cell cycle from G1 to S phase. Functional rescue experiment demonstrated that knockdown of MTBP attenuated C9orf142-mediated tumour growth and metastasis. Furthermore, depletion of C9orf142 remarkably increased the responsiveness of TNBC cells to CDK4/6 inhibitor abemaciclib. CONCLUSIONS: Together, these findings unveil a previously unrecognized effect of C9orf142 in TNBC progression and responsiveness to CDK4/6 inhibitor, and emphasize C9orf142 as a promising intervention target for TNBC treatment.

Investigating the relationship between inhibitory control and dietary adherence among patients with type 2 diabetes mellitus based on subjective and objective measures.

BACKGROUND: Dietary management has been recommended as the cornerstone of type 2 diabetes mellitus (T2DM) management. However, low adherence to dietary recommendations has been identified in both developed and developing countries. Previous research suggests that inhibitory control influences eating behavior, but few studies have been conducted in patients with T2DM. Thus, we aimed to explore the relationship between inhibitory control and dietary adherence among patients with T2DM. METHODS: A total of 393 patients with T2DM from the endocrinology departments of three tertiary hospitals in China were enrolled by the convenience sampling method. Dietary adherence was measured by the Dietary Behavior Adherence Scale for Patients with Type 2 Diabetes Mellitus. Additionally, inhibitory control was subjectively measured by the Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A) and objectively assessed by the stop signal task (SST) and the Stroop task. The relationship between inhibitory control and dietary adherence was analyzed using Pearson correlation analysis and hierarchical regression analysis. RESULTS: Subjectively measured inhibitory control had a significant predictive effect for dietary adherence after controlling for demographic and clinical variables. Adding the inhibitory control variable to the regression equation resulted in the following values: overall model F (19, 373) = 7.096, p < 0.001, increase in R2 value by 0.069, change in F (1, 373) = 35.219, p < 0.001. Similarly, the performance of the Stroop task had a significant predictive effect for dietary adherence to some foods, i.e., carbohydrate and fat. Adding the Stroop effect variable to the regression equation resulted in the following values: overall model F (19, 81) = 2.848, p = 0.005, increase in R2 value by 0.060, change in F (1, 81) = 8.137, p = 0.006. CONCLUSIONS: Inhibitory control was a predictor of dietary adherence in patients with T2DM. Future interventions should investigate whether inhibitory control training results in the improvement of dietary adherence in patients with T2DM.

ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling.

Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB.

The Relationship between Trait Impulsivity and Everyday Executive Functions among Patients with Type 2 Diabetes Mellitus: The Mediating Effect of Negative Emotions.

Background: In recent years, the incidence of type 2 diabetes mellitus (T2DM) has dramatically increased, imposing a heavy financial burden on society and individuals. The most cost-effective way to control diabetes is diabetes self-management, which depends on patients' executive functions (EFs). However, the level of EFs among patients with T2DM varies greatly. In addition to diabetes-related factors contributing to a decline in EFs, trait impulsivity as a relatively stable personality trait may explicate individual differences in EFs. The objective of this study was to verify the mediating effect of negative emotions on the relationship between trait impulsivity and EFs among patients with T2DM in China. Methods: A total of 305 patients with T2DM were enrolled consecutively from the endocrinology departments of three tertiary hospitals in China using convenience sampling. The participants completed the Sociodemographic Questionnaire, Mini-Mental State Examination (MMSE), Barratt Impulsiveness Scale-Brief (BIS-Brief), Depression Anxiety and Stress Scales with 21 items (DASS-21), and Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) version. A structural equation modeling was used to verify the mediating effect of negative emotions on the relationship between trait impulsivity and EFs. Results: A total of 32.46% of the participants experienced at least one aspect of daily EF decline. The mediating effect of trait impulsivity on the Behavioral Regulation Index (BRI) of EFs through negative emotions was significant, accounting for 29.57% of the total effect. The mediating effect of trait impulsivity on the Metacognitive Index (MI) of EFs through negative emotions was significant, accounting for 31.67% of the total effect. Conclusions: Trait impulsivity can positively predict EF decline, which can be alleviated by improving the negative emotions of patients with T2DM. Future research exploring interventions to improve the EFs of patients with T2DM should therefore consider their trait impulsivity and negative emotions.

Microstructure, Mechanical Properties, In Vitro Biodegradability, and Biocompatibility of Mg-Zn/HA Composites for Biomedical Implant Applications.

Recently, Mg-Zn/hydroxyapatite (HA) composites have attracted much attention as potential candidates for use in bone implants. In this paper, the MgZn/HA composites were prepared using powder metallurgy (PM) and the merging mechanism of MgZn and HA particles was investigated by adjusting the weight ratio of the HA powder. The evolution of the HA distribution in the matrix was examined using SEM and micro-CT images. Afterward, the mechanical properties and biocompatibility of the composites were discussed in detail. The results revealed that the mechanical properties and biocompatibility of the Mg-Zn/HA composites were significantly affected by the HA content. Composites with a low HA content showed increased porosity, improved mechanical strength, and enhanced corrosion resistance after ball milling and cold pressing. These results underscore the importance of optimizing the HA content in Mg-Zn/HA composites for bone implants. Based on our findings, PM Mg-Zn/HA composites with a moderate HA content demonstrate the most promising characteristics as bone implants. The insights gained from this work contribute to the advancement of bone implant materials and hold great potential for enhancing orthopedic surgery outcomes.

Network analysis of affect, emotion regulation, psychological capital, and resilience among Chinese males during the late stage of the COVID-19 pandemic.

Background: Previous studies have confirmed that both affect and emotion regulation strategies are closely associated with psychological capital (PsyCap) and resilience. These factors are assumed to buffer the effect of the COVID-19 pandemic on mental health, especially among males. However, these interactions have not been closely examined to date. To fill this gap, this paper explores the dimension-level relationships of these psychological constructs among Chinese males during the late stage of the COVID-19 pandemic and identified critical bridge dimensions using network analysis. Methods: A total of 1,490 Chinese males aged 21-51 years completed self-report scales assessing emotion regulation strategies, affect, PsyCap, and psychological resilience. Two regularized partial correlation networks, namely the affect and emotion regulation-PsyCap network and the affect and emotion regulation-psychological resilience network, were then constructed to examine links between the dimensions of these constructs. The bridge expected influence (BEI) index was also calculated for each node to identify important bridge nodes. Results: Positive affect, negative affect, cognitive reappraisal, and expressive suppression showed distinct and complex links to various dimensions of PsyCap or psychological resilience. In both networks, positive affect, cognitive reappraisal, and negative affect were identified as critical bridge nodes, with the first two having positive BEI values and the third having a negative value. Conclusion: The findings elucidate the specific role of the dimensions of emotion regulation or affect in relation to PsyCap and psychological resilience, which facilitates further understanding of the mechanisms underlying these interrelationships. These findings also provide implications for developing effective intervention strategies to increase PsyCap and psychological resilience.

MYC-driven U2SURP regulates alternative splicing of SAT1 to promote triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC), although highly lethal, lacks validated therapeutic targets. Here, we report that U2 snRNP-associated SURP motif-containing protein (U2SURP), a poorly defined member of the serine/arginine rich protein family, was significantly upregulated in TNBC tissues, and its high expression was associated with poor prognosis of TNBC patients. MYC, a frequently amplified oncogene in TNBC tissues, enhanced U2SURP translation through an eIF3D (eukaryotic translation initiation factor 3 subunit D)-dependent mechanism, resulting in the accumulation of U2SURP in TNBC tissues. Functional assays revealed that U2SURP played an important role in facilitating tumorigenesis and metastasis of TNBC cells both in vitro and in vivo. Intriguingly, U2SURP had no significant effects on proliferative, migratory, and invasive potential of normal mammary epithelial cells. Furthermore, we found that U2SURP promoted alternative splicing of spermidine/spermine N1-acetyltransferase 1 (SAT1) pre-mRNA by removal of intron 3, resulting in an increase in the stability of SAT1 mRNA and subsequent protein expression levels. Importantly, spliced SAT1 promoted the oncogenic properties of TNBC cells, and re-expression of SAT1 in U2SURP-depleted cells partially rescued the impaired malignant phenotypes of TNBC cells caused by U2SURP knockdown both in vitro and in mice. Collectively, these findings reveal previously unknown functional and mechanism roles of the MYC-U2SURP-SAT1 signaling axis in TNBC progression and highlight U2SURP as a potential therapy target for TNBC.

The impact of social distance on the processing of social evaluation: evidence from brain potentials and neural oscillations.

Previous research indicates that social distance can influence people's social evaluations of others. Individuals tend to evaluate intimate others more positively than distant others. The present study investigates the modulating effect of social distance on the time course underlying individuals' evaluation processes of others using adequate electroencephalography methods. The results reveal that in the initial processing stage, the P2 component is larger when friends are negatively evaluated, whereas this pattern is the opposite for strangers. In the second stage, medial frontal negativity and early mid-frontal theta band activity is enhanced for negative evaluations of friends, whereas this effect is absent in social evaluations of strangers. At the late stage, the P3 is larger for positive evaluations of friends but insensitive to social evaluations of strangers, and the late mid-frontal theta is also modulated by social distance. These findings provide direct and powerful evidence that social distance modulates individuals' evaluations of others with different levels of intimacy throughout all processing stages.

Destabilization of microrchidia family CW-type zinc finger 2 via the cyclin-dependent kinase 1-chaperone-mediated autophagy pathway promotes mitotic arrest and enhances cancer cellular sensitivity to microtubule-targeting agents.

BACKGROUND: Microtubule-targeing agents (MTAs), such as paclitaxel (PTX) and vincristine (VCR), kill cancer cells through activtion of the spindle assembly checkpoint (SAC) and induction of mitotic arrest, but the development of resistance poses significant clinical challenges. METHODS: Immunoblotting and RT-qPCR were used to investigate potential function and related mechanism of MORC2. Flow cytometry analyses were carried out to determine cell cycle distribution and apoptosis. The effect of MORC2 on cellular sensitivity to PTX and VCR was determined by immunoblotting, flow cytometry, and colony formation assays. Immunoprecipitation assays and immunofluorescent staining were utilized to investigate protein-protein interaction and protein co-localization. RESULTS: Here, we identified microrchidia family CW-type zinc finger 2 (MORC2), a poorly characterized oncoprotein, as a novel regulator of SAC activation, mitotic progression, and resistance of cancer cells to PTX and VCR. Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. Degradation of MORC2 during mitosis leads to SAC activation through stabilizing anaphase promoting complex/cyclosome activator protein Cdc20 and facilitating mitotic checkpoint complex assembly, thus contributing to mitotic arrest induced by PTX and VCR. Notably, knockdown of MORC2 promotes mitotic arrest induced by PTX and VCR and enhances the sensitivity of cancer cells to PTX and VCR. CONCLUSIONS: Collectively, these findings unveil a previously unrecognized function and regulatory mechanism of MORC2 in mitotic progression and resistance of cancer cells to MTAs. These results also provide a new clue for developing combined treatmentstrategy by targeting MORC2 in combination with MTAs against human cancer.

Transcranial Random Noise Stimulation Boosts Early Motion Perception Learning Rather than the Later Performance Plateau.

The effect of transcranial random noise stimulation (tRNS) on visual perceptual learning has only been investigated during early training sessions, and the influence of tRNS on later performance is unclear. We engaged participants first in 8 days of training to reach a plateau (Stage 1) and then in continued training for 3 days (Stage 2). In the first group, tRNS was applied to visual areas of the brain while participants were trained on a coherent motion direction identification task over a period of 11 days (Stage 1 + Stage 2). In the second group, participants completed an 8-day training period without any stimulation to reach a plateau (Stage 1); after that, they continued training for 3 days, during which tRNS was administered (Stage 2). In the third group, participants completed the same training as the second group, but during Stage 2, tRNS was replaced by sham stimulation. Coherence thresholds were measured three times: before training, after Stage 1, and after Stage 2. Compared with sham simulation, tRNS did not improve coherence thresholds during the plateau period. The comparison of learning curves between the first and third groups showed that tRNS decreased thresholds in the early training stage, but it failed to improve plateau thresholds. For the second and third groups, tRNS did not further enhance plateau thresholds after the continued 3-day training period. In conclusion, tRNS facilitated visual perceptual learning in the early stage, but its effect disappeared as the training continued.

Influence of empathy on work alienation among Chinese nurses during the COVID-19 pandemic: The mediating effect of ego depletion.

Background: Nurses' work alienation has become increasingly serious due to the increase in workload and risk during the coronavirus disease 2019 (COVID-19). However, no studies have investigated the link between empathy, ego depletion, and work alienation among Chinese nurses. The present study aimed to evaluate Chinese nurses' empathy, ego depletion, and work alienation and to examine whether nurses' ego depletion mediates the relationship between empathy and work alienation. Methods: This was a descriptive, cross-sectional study involving 353 nurses from Shaanxi. The Jefferson Scale of Empathy-Health Professionals, Self-Regulating Fatigue Scale and Work Alienation Questionnaire were used to collect data through an online survey. Structural equation modeling was conducted to analyze the mediating model. Results: Work alienation was negatively correlated with empathy (r = -0.305, p < 0.01) and positively correlated with ego depletion (r = 0.652, p < 0.01). Empathy was negatively correlated with ego depletion (r = -0.325, p < 0.01). Empathy can directly predict work alienation (ß = -0.263, p < 0.01), while ego depletion has a mediating effect between empathy and work alienation (ß = -0.309, p < 0.01), and the mediating effect accounts for 54.02% of the total effect. Conclusion: Nurses' work alienation was at a moderate-to-high level. Improving empathy can reduce work alienation through less ego depletion. Nursing managers should discover nurses' work alienation as soon as possible. Interventions to improve empathy can help replenish nurses' psychological resources, thereby reducing ego depletion and work alienation.

The Relationships Between Suicidal Ideation, Meaning in Life, and Affect: a Network Analysis.

Transitioning from holistic analysis to a fine-grained level analysis may provide further understanding of psychopathology. This study aimed to explore dimension-level relationships between suicidal ideation, meaning in life, and affect in a joint framework using network analysis and to identify potential prevention and intervention targets to address suicidal ideation. A total of 852 healthy adults aged 18-35 years completed self-report scales to assess suicidal ideation, meaning in life, and affect. A regularized partial correlation network was then built to examine the links between these dimensions. Expected influence and bridge expected influence values were calculated for each node. The prevalence of suicidal ideation was 4.2%. The search for and presence of meaning in life and positive and negative affect exhibited distinct and complex links to the three dimensions of suicidal ideation (pessimism, sleep, and despair). The important central nodes were search for meaning in life, sleep, despair, and positive affect, while the critical bridge nodes were positive affect, negative affect, and presence of meaning in life. These findings provide further understanding of the specific roles of meaning in life and affect in suicidal ideation. The identified nodes may be promising targets for prevention and intervention for suicidal ideation.

Ruthenium ion catalytic oxidation depolymerization of lignite under ultra-low dosage of RuCl3 catalyst and separation of the organic products with inorganic salts.

Depolymerization of lignite into valuable chemicals via ruthenium ion catalytic oxidation (RICO) is a potential route for the non-energy utilization of lignite. However, the high cost of the Ru catalyst during depolymerization and the high content of inorganic salts in the product solution limit the development of this route. In this work, RICO depolymerization of lignite was conducted under an ultra-low dosage of RuCl3 catalyst to decrease the usage of the catalyst during the RICO process. Different approaches were attempted to fulfill the separation of benzene polycarboxylic acids (BPCAs) products with the inorganic salts derived from the oxidant NaIO4, including butanone extraction and desalting via crystallization under different temperatures. The results show that lignite can be efficiently depolymerized under the mass ratio of RuCl3/lignite as low as 1/1000 by prolonging the reaction time without decreasing the depolymerization degree and BPCAs yields compared to the commonly used mass ratio of 1/10. Butanone can extract ca. 91% of the total BPCAs in the product solution, and the inorganic salts content (mainly NaIO3) in the extraction solution was as low as 0.19 mg mL-1. A new strategy of first acidification of depolymerization aqueous solution by HCl and then extraction by butanone is proved to be efficient for the separation of BPCAs with inorganic salts. Salting out via crystallization under lower temperature can remove ca. half content of the salts, and the efficiency is inferior to butanone extraction. The low usage of RuCl3 can efficiently decrease the catalyst cost of the RICO process, and butanone extraction can fulfill the enrichment of BPCAs and the separation of BPCAs with inorganic salts. This work is meaningful for the potential application of RCIO depolymerization of lignite for the production of valuable chemicals.

Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer.

Rationale: SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus, identifying new targets with site-specific SUMOylation and defining their biological functions will not only provide new mechanistic insights into the SUMOylation signaling but also open an avenue for developing new strategy for cancer therapy. MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme with an emerging role in the DNA damage response (DDR), but its regulatory mechanism remains enigmatic. Methods: In vivo and in vitro SUMOylation assays were used to determine the SUMOylation levels of MORC2. Overexpression and knockdown of SUMO-associated enzymes were used to detect their effects on MORC2 SUMOylation. The effect of dynamic MORC2 SUMOylation on the sensitivity of breast cancer cells to chemotherapeutic drugs was examined through in vitro and in vivo functional assays. Immunoprecipitation, GST pull-down, MNase, and chromatin segregation assays were used to explore the underlying mechanisms. Results: Here, we report that MORC2 is modified by small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 at lysine 767 (K767) in a SUMO-interacting motif dependent manner. MORC2 SUMOylation is induced by SUMO E3 ligase tripartite motif containing 28 (TRIM28) and reversed by deSUMOylase sentrin-specific protease 1 (SENP1). Intriguingly, SUMOylation of MORC2 is decreased at the early stage of DNA damage induced by chemotherapeutic drugs that attenuate the interaction of MORC2 with TRIM28. MORC2 deSUMOylation induces transient chromatin relaxation to enable efficient DNA repair. At the relatively late stage of DNA damage, MORC2 SUMOylation is restored, and SUMOylated MORC2 interacts with protein kinase CSK21 (casein kinase II subunit alpha), which in turn phosphorylates DNA-PKcs (DNA-dependent protein kinase catalytic subunit), thus promoting DNA repair. Notably, expression of a SUMOylation-deficient mutant MORC2 or administration of SUMO inhibitor enhances the sensitivity of breast cancer cells to DNA-damaging chemotherapeutic drugs. Conclusions: Collectively, these findings uncover a novel regulatory mechanism of MORC2 by SUMOylation and reveal the intricate dynamics of MORC2 SUMOylation important for proper DDR. We also propose a promising strategy to sensitize MORC2-driven breast tumors to chemotherapeutic drugs by inhibition of the SUMO pathway.

Protein Phosphatase 1 Subunit PPP1R14B Stabilizes STMN1 to Promote Progression and Paclitaxel Resistance in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) represents the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective therapeutic targets. To identify novel approaches for targeting TNBC, we examined the role of protein phosphatases in TNBC progression and chemoresistance. Protein phosphatase 1 regulatory subunit 14B (PPP1R14B), a poorly defined member of the protein phosphatase 1 regulatory subunits, was aberrantly upregulated in TNBC tissues and predicted poor prognosis. PPP1R14B was degraded mainly through the ubiquitin-proteasome pathway. RPS27A recruited deubiquitinase USP9X to deubiquitinate and stabilize PPP1R14B, resulting in overexpression of PPP1R14B in TNBC tissues. Gain- and loss-of-function assays demonstrated that PPP1R14B promoted TNBC cell proliferation, colony formation, migration, invasion, and resistance to paclitaxel in vitro. PPP1R14B also induced xenograft tumor growth, lung metastasis, and paclitaxel resistance in vivo. Mechanistic investigations revealed that PPP1R14B maintained phosphorylation and stability of oncoprotein stathmin 1 (STMN1), a microtubule-destabilizing phosphoprotein critically involved in cancer progression and paclitaxel resistance, which was dependent on PP1 catalytic subunits α and γ. Importantly, the tumor-suppressive effects of PPP1R14B deficiency could be partially rescued by ectopic expression of wild-type but not phosphorylation-deficient STMN1. Moreover, PPP1R14B decreased STMN1-mediated α-tubulin acetylation, microtubule stability, and promoted cell-cycle progression, leading to resistance of TNBC cells to paclitaxel. Collectively, these findings uncover a functional and mechanistic role of PPP1R14B in TNBC progression and paclitaxel resistance, indicating PPP1R14B is a potential therapeutic target for TNBC. SIGNIFICANCE: PPP1R14B upregulation induced by RPS27A/USP9X in TNBC increases STMN1 activity, leading to cancer progression and paclitaxel resistance.

Inositol monophosphatase 1 (IMPA1) promotes triple-negative breast cancer progression through regulating mTOR pathway and EMT process.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by high heterogeneity and metabolic dysregulation. Inositol monophosphatase 1(IMPA1) is critical for the metabolism of inositol, which has profound effects on gene expression and other biological processes. Here, we report for the first time that IMPA1 was upregulated in TNBC cell lines and tissues, and enhanced cell colony formation and proliferation in vitro and tumorigenicity in vivo. Additionally, IMPA1 promoted cell motility in vitro and metastatic lung colonization in vivo. Mechanistic investigations by transcriptome sequencing revealed that 4782 genes were differentially expressed between cells with IMPA1 knockdown and control cells. Among the differentially expressed genes after IMPA1 knockdown, five significantly altered genes were verified via qRT-PCR assays. Morerover, we found that the expression profile of those five targets as a gene set was significantly associated with IMPA1 status in TNBC cells. As this gene set was associated with mTOR pathway and epithelial-mesenchymal transition (EMT) process, we further confirmed that IMPA1 induced mTOR activity and EMT process, which at least in part contributed to IMPA1-induced TNBC progression. Collectively, our findings reveal a previously unrecognized role of IMPA1 in TNBC progression and identify IMPA1 as a potential target for TNBC therapy.

TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the lack of effective targeted therapies. Transmembrane (TMEM) proteins represent attractive drug targets for cancer therapy, but biological functions of most members of the TMEM family remain unknown. Here, we report for the first time that TMEM63A (transmembrane protein 63A), a poorly characterized TMEM protein with unknown functions in human cancer, functions as a novel oncogene to promote TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung metastasis in vivo. Mechanistic investigations revealed that TMEM63A localizes in endoplasmic reticulum (ER) and lysosome membranes, and interacts with VCP (valosin-containing protein) and its cofactor DERL1 (derlin 1). Furthermore, TMEM63A undergoes autophagy receptor TOLLIP-mediated autophagic degradation and is stabilized by VCP through blocking its lysosomal degradation. Strikingly, TMEM63A in turn stabilizes oncoprotein DERL1 through preventing TOLLIP-mediated autophagic degradation. Notably, pharmacological inhibition of VCP by CB-5083 or knockdown of DERL1 partially abolishes the oncogenic effects of TMEM63A on TNBC progression both in vitro and in vivo. Collectively, these findings uncover a previously unknown functional and mechanistic role for TMEM63A in TNBC progression and provide a new clue for targeting TMEM63A-driven TNBC tumors by using a VCP inhibitor.Abbreviations: ATG16L1, autophagy related 16 like 1; ATG5, autophagy related 5; ATP5F1B/ATP5B, ATP synthase F1 subunit beta; Baf-A1, bafilomycin A1; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CANX, calnexin; DERL1, derlin 1; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; HSPA8, heat shock protein family A (Hsp70) member 8; IP, immunoprecipitation; LAMP2A, lysosomal associated membrane protein 2; NBR1, NBR1 autophagy cargo receptor; OPTN, optineurin; RT-qPCR, reverse transcription-quantitative PCR; SQSTM1/p62, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TMEM63A, transmembrane protein 63A; TNBC, triple-negative breast cancer; TOLLIP, toll interacting protein; VCP, valosin containing protein.