Trends in suicide mortality among prostate cancer survivors in the United States, 1975-2019.

BACKGROUND: Suicide was an important cause of death in prostate cancer. This study intended to investigate trends in suicide mortality among prostate cancer (PCa) survivors from 1975 to 2019 in the United States. METHOD: We identified PCa survivors from the Surveillance, Epidemiology, and End Results (SEER) program from January 1975 to December 2019. Standardized mortality rate (SMR) was calculated d to assess the relative risk of suicide in PCa survivors compared with the general men population. Poisson regression model was performed to test for trend of SMRs. The cumulative mortality rate of suicide was calculated to assess the clinical burden of suicide mortality. RESULTS: 7108 (0.2%) cases were death from suicide cause, and 2,308,923(65.04%%) cases recorded as dying from non-suicidal causes. Overall, a slightly higher suicide mortality rate among PCa survivors was observed compared with general male population (SMR: 1.15, 95%CI: 1.09-1.2). The suicide mortality rate declined significantly relative to the general population by the calendar year of diagnosis, from an SMR of 1.74(95%CI: 1.17-2.51) in 1975-1979 to 0.99(0.89-1.1) in 2015-2019 (Ptrend < 0.001). PCa survivors with aged over 84 years, black and other races, registered in registrations (including Utah, New Mexico, and Hawaii) failed to observe a decrease in suicide mortality (Ptrend > 0.05). The cumulative suicide mortality during 1975-1994 was distinctly higher than in 1995-2019(P < 0.001). CONCLUSION: The trend in suicide mortality declined significantly from 1975 to 2019 among PCa survivors compared with the general male population in the United States. Notably, part of PCa survivors had no improvement in suicide mortality, and additional studies in the future were needed to explore it.

Marked increase in tumor transfection with a truncated branched polymer.

BACKGROUND: We previously determined that polyplexes formed by linear H2K peptides were more effective in transfecting tumors in vivo than polyplexes formed by branched H2K4b-20 peptides. Based on trypsin digest and salt displacement studies, the linear H2K polyplexes were less stable than the branched H2K4b-20 polyplexes. Because binding and release of the polymer and DNA from the H2K4b-20 polyplex may account for the ineffectiveness, we investigated whether four-branched histidine-lysine (HK) peptides with varying numbers of amino acids in their branches would be more effective in their ability to increase gene expression in tumors in vivo. METHODS: Linear and branched peptides with multiple -KHHK- motifs were synthesized by solid-phase synthesis. The branched H2K4b-20, -18, -14 and 12 peptides had 20, 18, 14 and 12 amino acids in their branches, respectively. These peptides were examined for their ability to carry luciferase-expressing plasmids to human breast cancer xenografts in a mouse model. With gel retardation and in vivo transfection, the incorporation of a targeting ligand and an endosomal lysis peptide into these polyplexes was also examined. A blocking antibody was pre-injected prior to the polyplexes to determine the role of neuropilin 1 in the uptake of these polyplexes by the tumor. The size of the polyplexes was measured by dynamic light scattering. RESULTS: Of the four negative surface-charge polyplexes formed by the branched carriers, the H2K4b-14 polyplex was determined to be the most effective plasmid delivery platform to tumors. The incorporation of a targeting ligand and an endosomal lysis peptide into H2K4b-14 polyplexes further enhanced their ability to transfect tumors in vivo. Furthermore, after pre-injecting tumor-bearing mice with a blocking antibody to the neuropilin-1 receptor (NRP-1), there was a marked reduction of tumor gene expression with the modified H2K4b-14 polyplexes, suggesting that NRP-1 mediated their transport into the tumor. CONCLUSIONS: The present study established that branched peptides intermediate in length were very efficient in delivering plasmids to tumors in vivo.

Location of a single histidine within peptide carriers increases mRNA delivery.

BACKGROUND: Previously, we determined that four-branched histidine-lysine (HK) peptides were effective carriers of plasmids and small interfering RNA. In the present study, we compared several branched HK carriers and, in particular, two closely-related H3K4b and H3K(+H)4b peptides for their ability as carriers of mRNA. The H3K(+H)4b peptide differed from its parent analogue, H3K4b, by only a single histidine in each branch. METHODS: A series of four-branched HK peptides with varied sequences was synthesized on a solid-phase peptide synthesizer. The ability of these peptides to carry mRNA expressing luciferase to MDA-MB-231 cells was investigated. With gel retardation and heparin displacement assays, the stability of HK polyplexes was examined. We determined the intracellular uptake of HK polyplexes by flow cytometry and fluorescence microscopy. The size and polydispersity index of the polyplexes in several media were measured by dynamic light scattering. RESULTS: MDA-MB-231 cells transfected by H3K(+H)4b-mRNA polyplexes expressed 10-fold greater levels of luciferase than H3K4b polyplexes. With gel retardation and heparin displacement assays, the H3K(+H)4b polyplexes showed greater stability than H3K4b. Intracellular uptake and co-localization of H3K(+H)4b polyplexes within acidic endosomes were also significantly increased compared to H3K4b. Similar to H3K(+H)4b, several HK analogues with an additional histidine in the second domain of their branches were effective carriers of mRNA. When combined with DOTAP liposomes, H3K(+H)4b was synergistic in delivery of mRNA. CONCLUSIONS: H3K(+H)4b was a more effective carrier of mRNA than H3K4b. Mechanistic studies suggest that H3K(+H)4b polyplexes were more stable than H3K4b polyplexes. Lipopolyplexes formed with H3K(+H)4b markedly increased mRNA transfection.

HSP70 promotes tumor progression by stabilizing Skp2 expression in gastric cancer cells.

Gastric cancer (GC) has one of the highest tumor incidences worldwide. Heat shock protein 70 (HSP70) is highly expressed and plays a critical role in the occurrence, progression, metastasis, poor prognosis, and drug resistance of GC. However, the underlying mechanisms of HSP70 are not clear. To explore the regulatory role of HSP70 in GC, we performed cell counting kit-8 (CCK-8) and EdU staining assays to assess cell proliferation; immunohistochemistry and western blot analyses to assess protein expression; coimmunoprecipitation (Co-IP) assays to assess interactions between two proteins; and immunofluorescence to assess protein expression and localization. HSP70 was highly expressed in clinical samples from patients with GC and indicated a poor prognosis. HSP70 inhibition enhanced the sensitivity of GC cells to thermochemotherapy. Furthermore, we found that S phase kinase-associated protein 2 (Skp2) was highly expressed in GC and correlated with HSP70 in array data from The Cancer Genome Atlas (TCGA). Importantly, HSP70 inhibition promoted Skp2 degradation. Skp2 overexpression abrogated HSP70 inhibition-induced cell cycle arrest, suggesting that the role of HSP70 in GC depends on Skp2 expression. Our results illustrate a possible regulatory mechanism of HSP70 and may provide a therapeutic strategy for overcoming resistance to thermochemotherapy.

Targeting the KDM4B-AR-c-Myc axis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer.

The histone demethylase KDM4B functions as a key co-activator for the androgen receptor (AR) and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 methylation marks. Constitutively active androgen receptor confers anti-androgen resistance in advanced prostate cancer. However, the role of KDM4B in resistance to next-generation anti-androgens and the mechanisms of KDM4B regulation are poorly defined. Here we found that KDM4B is overexpressed in enzalutamide-resistant prostate cancer cells. Overexpression of KDM4B promoted recruitment of AR to the c-Myc (MYC) gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA, which regulates the sensitivity to next-generation AR-targeted therapy. Inhibition of KDM4B significantly inhibited prostate tumor cell growth in xenografts, and improved enzalutamide treatments through suppression of c-Myc. Clinically, KDM4B expression was found upregulated and to correlate with prostate cancer progression and poor prognosis. Our results revealed a novel mechanism of anti-androgen resistance via histone demethylase alteration which could be targeted through inhibition of KDM4B to reduce AR-dependent c-Myc expression and overcome resistance to AR-targeted therapies. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells.

Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.

The ubiquitinase ZFP91 promotes tumor cell survival and confers chemoresistance through FOXA1 destabilization.

The forkhead box A1 (FOXA1), one of the forkhead class of DNA-binding proteins, functions as a transcription factor and plays a vital role in cellular control of embryonic development and cancer progression. Downregulation of FOXA1 has reported in several types of cancer, which contributes to cancer cell survival and chemoresistance. However, the mechanism for FOXA1 downregulation in cancer remains unclear. Here, we report that the ubiquitination enzyme zinc finger protein 91 (ZFP91) ubiquitinates and destabilizes FOXA1, which promotes cancer cell growth. High level of ZFP91 expression correlates with low level of FOXA1 protein in human gastric cancer (GC) cell lines and patient samples. Furthermore, ZFP91 knockdown reduces FOXA1 polyubiquitination, which decreases FOXA1 turnover and enhances cellular sensitivity to chemotherapy. Taken together, our findings reveal ZFP91-FOXA1 axis plays an important role in promoting GC progression and provides us a potential therapeutic intervention in the treatment of GC.

Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy.

The histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability. Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.

STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling.

Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48-linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.

Down-regulation of TRPS1 stimulates epithelial-mesenchymal transition and metastasis through repression of FOXA1.

The tricho-rhino-phalangeal syndrome 1 gene (TRPS1), which was initially found to be associated with tricho-rhino-phalangeal syndrome, is critical for the development and differentiation of bone, hair follicles and kidney. However, its role in cancer progression is largely unknown. In this study, we demonstrated that down-regulation of TRPS1 correlated with distant metastasis, tumour recurrence and poor survival rate in cancer patients. TRPS1 was frequently down-regulated in high-metastatic cancer cell lines from the breast, colon and nasopharynx. Silencing of TRPS1 stimulated epithelial-mesenchymal transition (EMT), migration and invasion in vitro and metastasis in vivo, while TRPS1 over-expression exhibited the opposite effects. Using quantitative proteomics, FOXA1, a negative regulator of epithelial-mesenchymal transition (EMT), was shown to be down-regulated by TRPS1 knockdown. Ectopic expression of FOXA1 blocked the enhancement of EMT, migration and invasion induced by TRPS1 silencing. Mechanistically, TRPS1, acting as a transcription activator, directly induced FOXA1 transcription by binding to the FOXA1 promoter. We further showed that down-regulation of TRPS1 was induced by miR-373 binding to the 3' UTR of TRPS1. Over-expression of TRPS1, but not TRPS1 3' UTR, blocked the enhancement of migration and invasion induced by miR-373. Taken together, we consider that down-regulation of TRPS1 by miR-373, acting as a transcriptional activator, promotes EMT and metastasis by repressing FOXA1 transcription, expanding upon its previously reported role as a transcription repressor. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

ACK1 promotes gastric cancer epithelial-mesenchymal transition and metastasis through AKT-POU2F1-ECD signalling.

Amplification of the activated Cdc42-associated kinase 1 (ACK1) gene is frequent in gastric cancer (GC). However, little is known about the clinical roles and molecular mechanisms of ACK1 abnormalities in GC. Here, we found that the ACK1 protein level and ACK1 phosphorylation at Tyr 284 were frequently elevated in GC and associated with poor patient survival. Ectopic ACK1 expression in GC cells induced epithelial-mesenchymal transition (EMT) and promoted migration and invasion in vitro, and metastasis in vivo; the depletion of ACK1 induced the opposite effects. We utilized SILAC quantitative proteomics to discover that the level of the cell cycle-related protein ecdysoneless homologue (ECD) was markedly altered by ACK1. Overexpression of ECD promoted EMT, migration, and invasion in GC, similar to the effects of ACK1 overexpression. Silencing of ECD completely blocked the augmentation of ACK1 overexpression-induced EMT, migration, and invasion. Mechanistically, ACK1 phosphorylated AKT at Thr 308 and Ser 473 and activated the AKT pathway to up-regulate the transcription factor POU2F1, which directly bound to the promoter region of its novel target gene ECD and thus regulated ECD expression in GC cells. Furthermore, the phosphorylation levels of AKT at Thr 308 and Ser 473 and POU2F1 and ECD levels were positively associated with ACK1 levels in clinical GC specimens. Collectively, we have demonstrated that ACK1 promotes EMT, migration, and invasion by activating AKT-POU2F1-ECD signalling in GC cells. ACK1 may be employed as a new prognostic factor and therapeutic target for GC.

Design, synthesis, and biological activity evaluation of new tankyrase-2 directed inhibitors.

A new series of flavonoids and quinolone derivatives were designed, synthesized and, evaluated for their biological activity. Among them, compound 14e showed better inhibition potency against TNKS2 in comparison with G007-LK, one of the most potent preclinical stage TNKS inhibitor. Molecular docking results showed that 14e occupied both the adenosine and nicotinamide pockets and formed a hydrogen bond with Met1054 of TNKS2. This study provides a lead for the design and discovery of potent and selective TNKS2 inhibitors.

Causal relationship between prostate cancer and 12 types of cancers: multivariable and bidirectional Mendelian randomization analyses.

BACKGROUND: Previous observational studies have shown an association between certain cancers and the subsequent risk of prostate cancer (PCa). However, the causal relationship between these cancers and PCa is still unclear. This study aimed to investigate the causal relationship between 12 common cancers and the risk of PCa. METHODS: We employed genome-wide association studies (GWAS) to perform forward and reverse Mendelian randomization (MR) within two-sample frameworks. Furthermore, we conducted multivariable MR analyses to investigate the relationships between different types of cancer. In addition, multiple sensitivity analysis methods were employed to assess the robustness of our findings. RESULTS: Our univariable MR analysis showed that genetically predicted hematological cancer was associated with a reduced risk of PCa (OR: 0.911, 95% CI 0.89-0.922, P = 0.03). Furthermore, MR analysis demonstrates that genetically predicted occurrence of thyroid gland and endocrine gland cancer also raised the risk of PCa (all P < 0.05). Multivariable analysis showed that thyroid gland cancer exhibited a higher incidence of PCa (OR: 1.12, 95% CI: 1.08-1.16, P = 0.008). In the reverse MR analysis, we found no significant inverse causal associations between PCa and 12 types of cancers. CONCLUSION: In summary, this study provided insights into the causal relationships between various types of cancer and PCa. Hematological cancer was suggested to associate with a lower risk of PCa, while thyroid gland cancer and endocrine gland cancer might increase the risk. These findings contribute to the understanding of genetic factors related to PCa and its potential associations with other cancers.

The enigmatic interplay of immune cells and abnormal spermatozoa through Mendelian randomization.

PURPOSE: Abnormal spermatozoa significantly impact reproductive health, affecting fertility rates, potentially prolonging conception time, and increasing the risk of miscarriages. This study employs Mendelian randomization to explore their potential link with immune cells, aiming to reveal their potential causal association and wider implications for reproductive health. METHODS: We conducted forward and reverse Mendelian randomization analyses to explore the potential causal connection between 731 immune cell signatures and abnormal spermatozoa. Using publicly available genetic data, we investigated various immune signatures such as median fluorescence intensities (MFI), relative cell (RC), absolute cell (AC), and morphological parameters (MP). Robustness was ensured through comprehensive sensitivity analyses assessing consistency, heterogeneity, and potential horizontal pleiotropy. The MR study produced a statistically significant p-value of .0000684, Bonferroni-corrected for the 731 exposures. RESULTS: The Mendelian randomization analysis revealed strong indications of a reciprocal relationship between immune cell pathways and sperm integrity. When examining immune cell exposure, a potential causal link with abnormal sperm was observed in 35 different types of immune cells. Conversely, the reverse Mendelian randomization results indicated that abnormal sperm might causally affect 39 types of immune cells. These outcomes suggest a potential mutual influence between alterations in immune cell functionality and the quality of spermatozoa. CONCLUSION: This study highlights the close link between immune responses and sperm development, suggesting implications for reproductive health and immune therapies. Further research may offer crucial insights into male fertility and immune disorders.

Based on disulfidptosis, revealing the prognostic and immunological characteristics of renal cell carcinoma with tumor thrombus of vena cava and identifying potential therapeutic target AJAP1.

BACKGROUND: Patients with clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus have a poor prognosis, high surgical risk, and lack of targeted therapeutic agents. METHODS: Genes with consistent differential expression trends in tumor tissues and VTT groups were first screened, and then differential genes associated with disulfidptosis were found by correlation analysis. Subsequently, identifying ccRCC subtypes and constructing risk models to compare the differences in prognosis and the tumor microenvironment in different subgroups. Finally, constructing a nomogram to predict the prognosis of ccRCC and validate key gene expression levels in cells and tissues. RESULTS: We screened 35 differential genes related to disulfidptosis and identified 4 ccRCC subtypes. Risk models were constructed based on the 13 genes, and the high-risk group had a higher abundance of immune cell infiltration, tumor mutational load, and microsatellite instability scores, predicting high sensitivity to immunotherapy. The 1-year AUC = 0.869 for predicting OS by nomogram has a high application value. The expression level of the key gene AJAP1 was low in both tumor cell lines and cancer tissues. CONCLUSIONS: Our study not only constructed an accurate prognostic nomogram for ccRCC patients but also identified an AJAP1 biomarker as a potential biomarker for the disease.

Prognostic and tumor microenvironmental feature of clear cell renal cell carcinoma revealed by m6A and lactylation modification-related genes.

Background: Both lactylation and m6A modification have important implications for the development of clear cell renal cell carcinoma (ccRCC), and we aimed to use crosstalk genes of both to reveal the prognostic and immunological features of ccRCC. Methods: Our first step was to look for lactylation-related genes that differed between normal and tumor tissues, and then by correlation analysis, we found the genes associated with M6A. Following that, ccRCC subtypes will be identified and risk models will be constructed to compare the prognosis and tumor microenvironment among different subgroups. A nomogram was constructed to predict the prognosis of ccRCC, and in vitro, experiments were conducted to validate the expression and function of key genes. Results: We screened 100 crosstalk genes and identified 2 ccRCC subtypes. A total of 11 prognostic genes were screened for building a risk model. we observed higher immune scores, elevated tumor mutational burden, and microsatellite instability scores in the high-risk group. Therefore, individuals classified as high-risk would derive greater benefits from immunotherapy. The nomogram's ability to predict overall survival with a 1-year AUC of 0.863 demonstrates its significant practical utility. In addition, HIBCH was identified as a potential therapeutic target and its expression and function were verified by in vitro experiments. Conclusion: In addition to developing a precise prognostic nomogram for patients with ccRCC, our study also discovered the potential of HIBCH as a biomarker for the disease.

Value of the application of computed tomography-based radiomics for preoperative prediction of unfavorable pathology in initial bladder cancer.

OBJECTIVES: To construct and validate unfavorable pathology (UFP) prediction models for patients with the first diagnosis of bladder cancer (initial BLCA) and to compare the comprehensive predictive performance of these models. MATERIALS AND METHODS: A total of 105 patients with initial BLCA were included and randomly enrolled into the training and testing cohorts in a 7:3 ratio. The clinical model was constructed using independent UFP-risk factors determined by multivariate logistic regression (LR) analysis in the training cohort. Radiomics features were extracted from manually segmented regions of interest in computed tomography (CT) images. The optimal CT-based radiomics features to predict UFP were determined by the optimal feature filter and the least absolute shrinkage and selection operator algorithm. The radiomics model consist with the optimal features was constructed by the best of the six machine learning filters. The clinic-radiomics model combined the clinical and radiomics models via LR. The area under the curve (AUC), accuracy, sensitivity, specificity, positive and negative predictive value, calibration curve and decision curve analysis were used to evaluate the predictive performance of the models. RESULTS: Patients in the UFP group had a significantly older age (69.61 vs. 63.93 years, p = 0.034), lager tumor size (45.7% vs. 11.1%, p = 0.002) and higher neutrophil to lymphocyte ratio (NLR; 2.76 vs. 2.33, p = 0.017) than favorable pathologic group in the training cohort. Tumor size (OR, 6.02; 95% CI, 1.50-24.10; p = 0.011) and NLR (OR, 1.50; 95% CI, 1.05-2.16; p = 0.026) were identified as independent predictive factors for UFP, and the clinical model was constructed using these factors. The LR classifier with the best AUC (0.817, the testing cohorts) was used to construct the radiomics model based on the optimal radiomics features. Finally, the clinic-radiomics model was developed by combining the clinical and radiomics models using LR. After comparison, the clinic-radiomics model had the best performance in comprehensive predictive efficacy (accuracy = 0.750, AUC = 0.817, the testing cohorts) and clinical net benefit among UFP-prediction models, while the clinical model (accuracy = 0.625, AUC = 0.742, the testing cohorts) was the worst. CONCLUSION: Our study demonstrates that the clinic-radiomics model exhibits the best predictive efficacy and clinical net benefit for predicting UFP in initial BLCA compared with the clinical and radiomics model. The integration of radiomics features significantly improves the comprehensive performance of the clinical model.

CPT1A mediates chemoresistance in human hypopharyngeal squamous cell carcinoma via ATG16L1-dependent cellular autophagy.

Hypopharyngeal squamous cell carcinoma (HSCC) is a highly aggressive malignancy that constitutes approximately 95% of all hypopharyngeal carcinomas, and it carries a poor prognosis. The primary factor influencing the efficacy of anti-cancer drugs for this type of carcinoma is chemoresistance. Carnitine palmitoyltransferase 1A (CPT1A) has been associated with tumor progression in various cancers, including breast, gastric, lung, and prostate cancer. The inhibition or depletion of CPT1A can lead to apoptosis, curbing cancer cell proliferation and chemoresistance. However, the role of CPT1A in HSCC is not yet fully understood. In this study, we discovered that CPT1A is highly expressed in HSCC and is associated with an advanced T-stage and a poor 5-year survival rate among patients. Furthermore, the overexpression of CPT1A contributes to HSCC chemoresistance. Mechanistically, CPT1A can interact with the autophagy-related protein ATG16L1 and stimulate the succinylation of ATG16L1, which in turn drives autophagosome formation and autophagy. We also found that treatment with 3-methyladenine (3-MA) can reduce cisplatin resistance in HSCC cells that overexpress CPT1A. Our findings also showed that a CPT1A inhibitor significantly enhances cisplatin sensitivity both in vitro and in vivo. This study is the first to suggest that CPT1A has a regulatory role in autophagy and is linked to poor prognosis in HSCC patients. It presents novel insights into the roles of CPT1A in tumorigenesis and proposes that CPT1A could be a potential therapeutic target for HSCC treatment.

Deciphering the immunological and prognostic features of bladder cancer through platinum-resistance-related genes analysis and identifying potential therapeutic target P4HB.

Objectives: To identify the molecular subtypes and develop a scoring system for the tumor immune microenvironment (TIME) and prognostic features of bladder cancer (BLCA) based on the platinum-resistance-related (PRR) genes analysis while identifying P4HB as a potential therapeutic target. Methods: In this study, we analyzed gene expression data and clinical information of 594 BLCA samples. We used unsupervised clustering to identify molecular subtypes based on the expression levels of PRR genes. Functional and pathway enrichment analyses were performed to understand the biological activities of these subtypes. We also assessed the TIME and developed a prognostic signature and scoring system. Moreover, we analyzed the efficacy of immune checkpoint inhibitors. Then we conducted real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) experiments to detect the expression level of prolyl 4-hydroxylase subunit beta (P4HB) in BLCA cell lines. Transfection of small interference ribonucleic acid (siRNA) was performed in 5637 and EJ cells to knock down P4HB, and the impact of P4HB on cellular functions was evaluated through wound-healing and transwell assays. Finally, siRNA transfection of P4HB was performed in the cisplatin-resistant T24 cell to assess its impact on the sensitivity of BLCA to platinum-based chemotherapy drugs. Results: In a cohort of 594 BLCA samples (TCGA-BLCA, n=406; GSE13507, n=188), 846 PRR-associated genes were identified by intersecting BLCA expression data from TCGA and GEO databases with the PRR genes from the HGSOC-Platinum database. Univariate Cox regression analysis revealed 264 PRR genes linked to BLCA prognosis. We identified three molecular subtypes (Cluster A-C) and the PRR scoring system based on PRR genes. Cluster C exhibited a better prognosis and lower immune cell infiltration compared to the other Clusters A and B. The high PRR score group was significantly associated with an immunosuppressive tumor microenvironment, poor clinical-pathological features, and a poor prognosis. Furthermore, the high PRR group showed higher expression of immune checkpoint molecules and a poorer response to immune checkpoint inhibitors than the low PRR group. The key PRR gene P4HB was highly expressed in BLCA cell lines, and cellular functional experiments in vitro indicate that P4HB may be an important factor influencing BLCA migration and invasion. Conclusion: Our study demonstrates that the PRR signatures are significantly associated with clinical-pathological features, the TIME, and prognostic features. The key PRR gene, P4HB, s a biomarker for the individualized treatment of BLCA patients.

Targeting histone demethylases as a potential cancer therapy (Review).

Post­translational modifications of histones by histone demethylases have an important role in the regulation of gene transcription and are implicated in cancers. Recently, the family of lysine (K)­specific demethylase (KDM) proteins, referring to histone demethylases that dynamically regulate histone methylation, were indicated to be involved in various pathways related to cancer development. To date, numerous studies have been conducted to explore the effects of KDMs on cancer growth, metastasis and drug resistance, and a majority of KDMs have been indicated to be oncogenes in both leukemia and solid tumors. In addition, certain KDM inhibitors have been developed and have become the subject of clinical trials to explore their safety and efficacy in cancer therapy. However, most of them focus on hematopoietic malignancy. This review summarizes the effects of KDMs on tumor growth, drug resistance and the current status of KDM inhibitors in clinical trials.