Abstract Histone deacetylase 6 (HDAC6) has emerged as a critical regulator of tumor progression across multiple malignancies. Our integrated analyses reveal that environmental phthalates (BBP, DBP) drive oncogenic processes in breast epithelial stem cells and ER-negative breast cancer by activating ER-EGFR-PKA or AhR-cAMP-PKA-CREB1 signaling, leading to HDAC6 upregulation, β-catenin/LEF1-TCF4 activation, epithelial-mesenchymal transition (EMT), and enhanced metastatic potential. Beyond breast cancer, clinical datasets and functional studies demonstrate that elevated HDAC6 expression correlates with advanced stage, higher tumor grade, and poor survival in lung cancer, oral squamous cell carcinoma (OSCC), and endometriosis-associated ovarian carcinoma (EAOC). Mechanistically, HDAC6 promotes tumor progression by regulating HIF-1α/BNIP3-mediated autophagy in lung cancer, driving AP-1-dependent IL-13 expression and M2 macrophage polarization in OSCC, and mediating ARID1A mutation-associated IL-10-driven immunosuppressive macrophage programming in EAOC. Importantly, pharmacologic HDAC inhibition (TSA, vorinostat) suppresses autophagy, reverses macrophage polarization, reduces EMT, and markedly inhibits tumor growth in relevant in vitro and in vivo models. Together, these findings position HDAC6 as a convergent oncogenic and immunoregulatory hub across environmentally induced, hormone-independent, and mutation-associated cancers, supporting HDAC6-targeted therapies as a promising strategy for limiting tumor progression and reshaping the tumor immune microenvironment. Citation Format: Chia-Wei Wu, Chia-Yi Hsu, Eing-Mei Tsai, Tsung-Hua Hsieh. HDAC6 as a convergent oncogenic and immunoregulatory hub across multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3890.

Histone deacetylase 6 (HDAC6) plays an important role in the development and prognosis of lung cancer. Increasing evidence suggests that HDAC6-mediated regulation of autophagy may contribute to tumor progression and therapeutic resistance. However, the precise molecular mechanisms by which HDAC6 modulates autophagic pathways in lung cancer remain incompletely understood and warrant further investigation. In this study, clinical lung cancer specimens(N = 100) were analyzed, revealing that HDAC6 expression was significantly associated with tumor stage (P = 0.012) and tumor grade (P = 0.028). High expression of HDAC6 increased the survival risk of lung cancer patients by 3.652-fold and significantly reduced the survival rate (P ≤ 0.001). Our findings further demonstrate that HDAC6 modulates autophagy by regulating the HIF-1α/BNIP3 signaling pathway through its deacetylase activity. Moreover, pharmacological inhibition of HDAC with Trichostatin A (TSA) suppressed both HDAC6 and BNIP3 expression, decreased autophagic activity, and reduced lung tumor formation in a KRASG12D+/P53loxP/loxP transgenic mouse model. Collectively, these results reveal a novel HDAC6-HIF-1α-BNIP3 axis that governs autophagy in lung cancer and underscore the potential of HDAC6 as a therapeutic target for modulating autophagy and inhibiting lung tumor progression.

The Performance Evaluation Matrix (PEM) is an excellent decision-making tool for assessment and resource management. Satisfaction Index and Importance Index are two important evaluation indicators of construction and PEM. Managers can decide whether the service item needs to be improved based on the Satisfaction Index of the service item. When resources are limited, managers can determine the priority of improving the service item based on the Importance Index. In order to avoid the risk of misjudgment caused by sample errors and meet the needs of enterprises’ rapid decision-making, this study proposed a fuzzy test built on the confidence intervals of the above two key indicators to decide whether essential service items should be improved and determine the priority of improvement. Since the fuzzy test was relatively complex, this study further came up with fuzzy evaluation values and fuzzy evaluation critical values of service items following fuzzy testing rules. Besides, evaluation rules were established to facilitate industrial applications. This approach can be completed with any common word processing software, so it is relatively convenient in application and easy to manage. Finally, an application example was presented in this paper to explain the applicability of the proposed approach.

Breast cancer is the most common malignancy and its incidence is increasing. It is currently mainly treated by clinical chemotherapy, but chemoresistance remains poorly understood. Prefolded proteins 4 (PFDN4) are molecular chaperone complexes that bind to newly synthesized polypeptides and allow them to fold correctly to stabilize protein formation. This study aimed to investigate the role of PFDN4 in chemotherapy resistance in breast cancer. Our study found that PFDN4 was highly expressed in breast cancer compared to normal tissues and was statistically significantly associated with stage, nodal status, subclasses (luminal, HER2 positive and triple negative), triple-negative subtype and disease-specific survival by TCGA database analysis. CRISPR knockout of PFDN4 inhibited the growth of 89% of breast cancer cell lines, and the triple-negative cell line exhibited a stronger inhibitory effect than the non-triple-negative cell line. High PFDN4 expression was associated with poor overall survival in chemotherapy and resistance to doxorubicin and paclitaxel through the CREBP1/AURKA pathway in the triple-negative MDAMB231 cell line. This study provides insightful evidence for the value of PFDN4 in poor prognosis and chemotherapy resistance in breast cancer patients.

The earthquake disaster has an impact on tourist visit intention. This study aims to investigate tourist behavior in the post-earthquake disaster linkage between information sources (word of mouth and electronic word of mouth) and risk perception toward tourists' visit intentions to a destination in Indonesia. This study applies the SOR theory to predict tourists' behavior in the destination aftermath. The Partial Least Squares Structural Equation Model was used to examine the hypothesis of the study. The result found that information sources (electronic word of mouth and word of mouth) significantly influenced visit intention in the time of post-earthquake disaster. The risk perception has not significantly influenced visit intention in post-earthquake disasters. The discussion and conclusion of the study are discussed herein. Overall, the findings of the study may contribute to the theory by adding information sources to predict tourist behavior post-earthquake disaster and also gives a practical contribution to the tourism sector, stakeholders, tourism marketers, and policymakers in Indonesia to enhance the marketing strategy by considering destination promotion through word of mouth (offline) and electronic word of mouth (online) and its mechanism on tourists' travel decision in the time of aftermath.

Recently, information, communication, and technologies (ICTs) and the tourism sector have gained attention from researchers and practitioners. Thus, we examined the trends in using ICTs in the tourism sector using a scientific document approach based on bibliometric analysis. A bibliometric analysis was conducted on 102 selected papers from the Scopus database from 2000 to 2021. The results revealed that the most discussed keywords in the papers were ICT and destination management organization, smart tourism destination, and smart city. Co-occurrence analysis was performed to analyze the trending topic in ICTs, tourism, and hospitality used by academics, while authorship network collaboration examined the partnership between different countries around the world. Statistics such as the number of documents per country, number of citations related to each country, ICT practice studies, and research methods were also discussed in this study. Limitations and implications were also indicated to provide deeper insights to researchers and their future research in terms of ICTs, tourism, and hospitality.

Based on some studies, there are many important parts of tool machines, all of which have some essential smaller-the-better-type quality characteristics. The six sigma quality index of the smaller-the-better type offers accurate measurement of the process yield and the six sigma quality level. In this paper, we first proposed a six sigma product index by integrating all evaluation indicators for products that contain several quality characteristics of the smaller-the-better type. Next, we derived the confidence interval of this six sigma product index and developed an evaluation model for product quality. When a product passes the evaluation of this model, not only can it be guaranteed that the product reaches the required quality level, but also a high rate of product yield can be ensured. In addition, we also created a product improvement testing model, which can avoid missing opportunities for improvement in the process to ensure improvement effects. This complete evaluation and improvement model is applicable to the entire machine tool industry chain. It can not only increase the product value of the machine tool industry chain but also decrease environmental pollution caused by rework or scrap, which is beneficial to companies to enhance their image of fulfilling social responsibilities. Apart from the above advantages, the model formed in this paper is based on confidence intervals, thereby reducing the chance of misjudgment resulting from sampling error.

Endometriosis is a common disease in women and may be one of the factors that induces malignant epithelial ovarian tumors. Previous studies suggested that endometriosis is related to ARID1A mutation mediating the expression of HDAC6, but the detailed pathogenic mechanism is still unclear. First, we collected endometriosis-associated ovarian carcinoma (EAOC) clinical samples and examined the expression of HDAC6. Our results found that the high HDAC6 expression group was positively correlated with EAOC histology (P = 0.015), stage (P < 0.000), and tumor size (P < 0.000) and inversely correlated with survival (P < 0.000). We also found that ARID1A6488delG/HDAC6 induced M2 polarization of macrophages through IL-10. In addition, the HDAC inhibitor (HDACi) vorinostat inhibited cell growth and blocked the effect of HDAC6. Tomographic microscopy was used to monitor the live cell morphology of these treated cells, and we found that vorinostat treatment resulted in substantial cell apoptosis by 3 h 42 min. Next, we established a transgenic mouse model of EAOC and found that vorinostat significantly reduced the size of ovarian tumors by inhibiting M2 macrophage polarization in mice. Together, these data demonstrate that the signaling pathway of E4F1/ARID1A6488delG/HDAC6/GATA3 mediates macrophage polarization and provides a novel immune cell-associated therapeutic strategy targeting IL-10 in EAOC.

Taraxacum officinale (dandelion) is often used in traditional Chinese medicine for the treatment of cancer; however, the downstream regulatory genes and signaling pathways mediating its effects on breast cancer remain unclear. The present study aimed to explore the effects of luteolin, the main biologically active compound of T. officinale, on gene expression profiles in MDA-MB-231 and MCF-7 breast cancer cells. The results revealed that luteolin effectively inhibited the proliferation and motility of the MDA-MB-231 and MCF-7 cells. The mRNA expression profiles were determined using gene expression array analysis and analyzed using a bioinformatics approach. A total of 41 differentially expressed genes (DEGs) were found in the luteolin-treated MDA-MB-231 and MCF-7 cells. A Gene Ontology analysis revealed that the DEGs, including AP2B1, APP, GPNMB and DLST, mainly functioned as oncogenes. The human protein atlas database also found that AP2B1, APP, GPNMB and DLST were highly expressed in breast cancer and that AP2B1 (cut-off value, 75%) was significantly associated with survival rate (p = 0.044). In addition, a Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the DEGs were involved in T-cell leukemia virus 1 infection and differentiation. On the whole, the findings of the present study provide a scientific basis that may be used to evaluate the potential benefits of luteolin in human breast cancer. Further studies are required, however, to fully elucidate the role of the related molecular pathways.

Resistance to chemotherapy and hormonal therapy is a major clinical problem in breast cancer medicine, especially for cancer metastasis and recurrence. Di(2-ethylhexyl)phthalate (DEHP) affects drug resistance by an unknown mechanism of action. Here we analyzed breast cancer patients (N = 457) and found that Σ4MEHP (the sum of MEHP, MEHHP, MECPP and MEOHP concentrations) in urine was significantly higher (P = 0.018) in the recurrent breast cancer group compared with non-recurrent patients. Σ4MEHP-High was positively and significantly correlated with tumor stage (P = 0.005), lymph node status (P = 0.001), estrogen receptor status (P = 0.010), Her2/Neu status (P = 0.004), recurrence (P = 0.000) and tumor size (P = 0.002), as well as an independent prognostic marker (OR = 1.868; 95% CI = 1.424–2.451; P < 0.000) associated with poor survival rates based on a positive Her2/Neu status (P = 0.035). In addition, we found that DEHP inhibited paclitaxel and doxorubicin effects in breast cancer cell lines MCF-7 and MDA-MB-231 and in zebrafish and mouse tumor initiation models. DEHP induced trefoil factor 3 (TFF3) expression through the vinculin/aryl hydrocarbon receptor (AhR)/ERK signaling pathway and induced CYP2D6, CYP2C8 and CYP3A4 expression through the AhR genomic pathway to increase the epithelial-mesenchymal transition (EMT) and doxorubicin metabolism, respectably. DEHP mediated AhR-related alterations in estrogen receptor expression through the ubiquitination system, which decreased tamoxifen effects in AhR knockout mice. These findings suggest a novel therapeutic avenue by targeting AhR in drug-resistant and recurrent breast cancer.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor worldwide that is characterized by abnormal lesions or malignant hyperplasia of soft and hard tissues in the oral cavity. Previous research has found that HDAC6 may be a potential therapeutic target for cancer patients and has the ability to regulate immune cells. However, the mechanism of HDAC6 in OSCC pathogenesis is unclear. We collected clinical samples and analyzed the level of HDAC6 in OSCC patients. The results showed that in the high HDAC6 expression group, HDAC6 expression was positively correlated with the grade of OSCC (R = 0.182, P = 0.036) and that this group had a 3.248-fold increase in the mortality risk compared with the low HDAC6 expression group ( P = 0.003). Survival analysis also identified a correlation between the expression of HDAC6 and overall survival in OSCC patients, and it was found that the expression of HDAC6 was inversely correlated with survival ( P ≤ 0.001). In addition, we found that HDAC6 induced IL-13 expression through AP-1, resulting in M2 polarization of macrophages. Together, these results demonstrate that the level of HDAC6 may be a useful prognostic biomarker and offer a novel immune cell-related therapeutic strategy of targeting IL-13 in OSCC.

The new coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been reported and spread globally. There is an urgent need to take urgent measures to treat and prevent further infection of this virus. Here, we use virtual drug screening to establish pharmacophore groups and analyze the ACE2 binding site of the spike protein with the ZINC drug database and DrugBank database by molecular docking and molecular dynamics simulations. Screening results showed that Venetoclax, a treatment drug for chronic lymphocytic leukemia, has a potential ability to bind to the spike protein of SARS-CoV-2. In addition, our in vitro study found that Venetoclax degraded the expression of the spike protein of SARS-CoV-2 through amino acids Q493 and S494 and blocked the interaction with the ACE2 receptor. Our results suggest that Venetoclax is a candidate for clinical prevention and treatment and deserves further research.

The association between phthalate exposure and breast cancer remains controversial. We performed a prospective patient cohort design to explore the interaction between creatinine-corrected urinary phthalate metabolites and hormone receptors as well as body mass index (BMI) on recurrent breast cancer. In this follow-up study, 636 female breast cancer patients and 45 new recurrent cases diagnosed for a total of 1576.68 person-years of follow-up were recruited. Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively associated with breast cancer recurrence, with adjusted hazard ratio (aHR) 3rd vs. 1st quartile of 0.15 (95% CI 0.04–0.51). The MEOHP presented as a non-monotonic dose–response (NMDR) curve, being U-shaped. In the stratification of hormone receptors, MEOHP still exhibited a U-shaped dose–response curve. The third quartile of MEOHP showed significant lowest recurrent risk in the status of ER-positive (aHR 0.18, 95% CI 0.05–0.66), PR-negative (aHR 0.14, 95% CI 0.03–0.63), and HER2-negative (aHR 0.24, 95% CI 0.08–0.76). Whether in BMI < 25 or in BMI ≥ 25, the third quartile of MEOHP was negatively associated with recurrent breast cancer, and there was a negative interaction on an additive scale between MEOHP and BMI (pinteraction = 0.042). The association between MEOHP and recurrent breast cancer was modified by hormone receptors and BMI.

The sports lottery industry is growing globally, especially in the online betting market. This study focuses on online sports lottery behavior and tries to propose a framework applied in a virtual environment. Based on the Technology Acceptance Model, four antecedes (subject norm, computer anxiety, computer self-efficacy, and personal innovativeness) are added to this framework. The subjects of this study, from whom 268 valid questionnaires were collected, were betting members of sports lottery venders in the Taichung district. Findings show that subject norm is a good antecede in this framework, but computer anxiety does not reach statistical significance for explanation in this study. Both computer self-efficacy and personal innovativeness positively influence perceived usefulness. The results demonstrate the value of the expanded TAM and use of the expanded model indicates a high degree of acceptance for online betting systems among sports lottery consumers. The TAM expansion proved relevant in gathering applied information on the behavior of sports lottery consumers.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world, and the incidence and death rate of OSCC in men is twice that of women. CD47 is a ubiquitous cell surface transmembrane protein, also known as integrin-related protein (IAP). Previous studies have pointed out that CD47 can inhibit the growth of OSCC, but the detailed mechanism is not clear. This study aimed to explore the effect of CD47 gene expression profiles in OSCC. The OSCC cell lines, OECM-1 and OC-2, overexpressed CD47, and the expression profiles of mRNAs were analyzed through next-generation sequencing (NGS) with a bioinformatic approach. A total of 14 differentially expressed genes (DEGs) were listed. In addition, ingenuity pathway analysis (IPA) was used to analyze the molecular function (MF), biological process (BP), and cellular component (CC) network signaling. The human protein atlas (HPA) database was used to analyze gene expression and the survivability of human cancer. The results found that HSPA5, HYOU1, and PDIA4 were involved in the IPA network and when highly expressed, mediated the survivability of cancer. In addition, HSPA5 was positively and significantly correlated with CD47 expression (p < 0.0001) and induced by CD47-overexpression in the OECM-1 and OC-2 OSCC cancer cell lines. These findings provide important insights into possible new diagnostic strategies, including unfolded protein for OSCC-targeting CD47.

Cancer stem cells (CSCs) are subpopulations of tumor masses with unique abilities in self-renewal, stemness maintenance, drug resistance, and the promotion of cancer recurrence. Recent studies have suggested that breast CSCs play essential roles in chemoresistance. Therefore, new agents that selectively target such cells are urgently required. Reactive oxygen species (ROS)-producing enzymes are the reason for an elevated tumor oxidant status. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor, which upon detecting cellular oxidative stress, binds to the promoter region of antioxidant genes. By triggering a cytoprotective response, Nrf2 maintains cellular redox status. Cripto-1 participates in the self-renewal of CSCs. Herein, luteolin, a flavonoid found in Taraxacum officinale extract, was determined to inhibit the expressions of stemness-related transcriptional factors, the ATP-binding cassette transporter G2 (ABCG2), CD44, aldehyde dehydrogenase 1 activity as well as the sphere formation properties of breast CSCs. Furthermore, luteolin suppressed the protein expressions of Nrf2, heme oxygenase 1 (HO-1), and Cripto-1 which have been determined to contribute critically to CSC features. The combination of luteolin and the chemotherapeutic drug, Taxol, resulted in enhanced cytotoxicity to breast cancer cells. These findings suggest that luteolin treatment significantly attenuated the hallmarks of breast cancer stemness by downregulating Nrf2-mediated expressions. Luteolin constitutes a potential agent for use in cancer stemness-targeted breast cancer treatments.

Context: Small extracellular vesicles (sEVs) have emerged as modulators of the disease microenvironment, thereby supporting disease progression. However, the potential role of EVs and their content to the pathophysiology of endometriosis remain unclear. Objective: This work aimed to investigate whether the EVs from eutopic (Eu) and ectopic (Ec) endometrial stromal cells (ESCs) differ with respect to protein composition and role in endometriosis. Methods: Human Eu and Ec endometrium-derived ESCs were isolated from samples of the same patients (n = 3). sEVs were isolated from ESCs via ultracentrifugation; these sEVs were characterized by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis and analyzed using mass spectrometry. The potential role of EcESCs-derived sEVs (EcESCs-sEVs) in endometriosis was explored by assaying their effects on cell viability/proliferation, migration, and angiogenesis. Results: In total, 105 ESCs-sEV-associated proteins were identified from EcESCs-sEVs and EuESCs-sEVs by mass spectrometry analysis. The protein content differed between EcESCs-sEVs and EuESCs-sEVs, with annexin A2 (ANXA2) being the most prominent difference-present in EcESCs-sEVs but not EuESCs-sEVs. We also found that sEVs-ANXA2 regulates the motility, proliferation, and angiogenesis of ESCs via the extracellularly regulated kinase (ERK)/STAT3 pathway. Notably, treatment of ESCs with sEVs-ANXA2 resulted in increased proliferation and motility, suggesting that sEVs-ANXA2 may be involved in regulating endometriosis. Our data suggest that EcESCs-sEVs-ANXA2 regulates the motility and the angiogenic potential of ESCs, implying a role for sEVs-ANXA2 in the pathogenesis of endometriosis. Conclusion: The study of sEVs-ANXA2 from Ec endometriotic cells uncovers a new mechanism of endometriosis progression and will inform the development of novel therapeutic strategies.

It has been identified that bisphenol A (BPA) exposure causes developmental toxicity in breast cells. However, the exact molecular mechanisms underlying the association between exposure to BPA and breast cancer remain unclear. The aim of the present study was to investigate the BPA-regulated signaling pathways associated with the aggressiveness and the development of breast cancer. Microarray technology and functional gene set analyses were used to evaluate BPA and breast cancer-associated biomarkers and pathways in a discovery-driven manner. Using individual dataset analyses, it was indicated that two BPA-associated gene sets, the visceral obesity pathway, involved in visceral fat deposits and the metabolic syndrome, and the cell cycle pathway, involved in cyclins and cell cycle regulation, were significantly associated with a high grade of aggressiveness and the development of estrogen receptor (ER)-positive breast cancer (between P<0.05 and 0.0001). The pooled analysis indicated that the most significant pathway was G1/S checkpoint regulation, and the cyclin and cell cycle regulation pathway for BPA-associated ER-positive cancer. Cancer cell signaling pathways were associated with healthy breast cells developing into breast cancer. The visceral obesity and the cell cycle pathways were indicated to link BPA exposure to breast cancer. The results of the present study demonstrate a significant association between breast cancer and BPA-regulated gene pathways.

Helicobacter pylori infection is an important pathogenic risk factor for gastric cancer, but it is still unclear what tumor markers for gastric cancer induced by H. pylori can be consistently detected. Using an miRNA microarray, we found that miR-18a-3p (6.02-fold) and miR-4286 (5.73-fold) were significantly increased in H. pylori― associated gastric cancer. In a cohort of gastric cancer patients (N = 104), serum expression of miR-18a-3p and miR-4286 was positively and significantly correlated with H. pylori; furthermore, miR-18a-3p was positively correlated with invasion (P = 0.029), and miR-4286 was positively correlated with tumor stage (P = 0.033), tumor size (P = 0.041), and lymph node metastasis (P = 0.009). Overexpression of miR-18a-3p and miR-4286 also increased cancer cell proliferation and motility and both inhibited expression of BZRAP1, resulting in tumor progression in vitro. In addition, lipopolysaccharide co-mediated the expression of miR-18a-3p and miR-4286 by activating the NF-κB transcription factor, but TAK-242 (TLR4 inhibitor) blocked this effect. These results demonstrate that serum miR-18a-3p and miR-4286 levels in H. pylori―associated gastric cancer may be useful prognostic biomarkers and suggest a novel signaling pathway of targeting BZRAP1 in gastric cancer.

Mutant RAS genes play an important role in regulating tumors through lysine residue 104 to impair GEF-induced nucleotide exchange, but the regulatory role of KRAS K104 modification on the KRASG12D mutant remains unclear. Therefore, we simulated the acetylation site on the KRASG12D three-dimensional protein structure, including KRASG12D, KRASG12D/K104A and KRASG12D/K104Q, and determined their trajectories and binding free energy with GEF. KRASG12D/K104Q induced structural changes in the α2- and α3-helices, promoted KRAS instability and hampered GEF binding (ΔΔG = 6.14 kJ/mol). We found decreased binding to the Raf1 RBD by KRASG12D/K104Q and reduced cell growth, invasion and migration. Based on whole-genome cDNA microarray analysis, KRASG12D/K104Q decreased expression of NPIPA2, DUSP1 and IL6 in lung and ovarian cancer cells. This study reports computational and experimental analyses of Lys104 of KRASG12D and GEF, and the findings provide a target for exploration for future treatment.