ABSTRACT
Abnormalities in the extracellular matrix (ECM) play important roles in the regulation and progression of clear cell renal cell carcinoma (ccRCC). The cysteine cathepsin is one of the major proteases involved in ECM remodeling and has been shown to be aberrantly expressed in multiple cancer types. However, the clinical significance and biological function of distinct cysteine cathepsins in ccRCC remain poorly understood. In this study, several bioinformatics databases, including UALCAN, TIMER, GEPIA and the Human Protein Atlas datasets, were used to analyze the expression and prognostic value of different cysteine cathepsin family members in ccRCC. We found that the expression level of CTSF was downregulated in tumor tissues and closely related to the poor survival of ccRCC patients. Further in vitro experiments suggested that CTSF overexpression suppressed the proliferation and migration of ccRCC cells. Moreover, the expression of CTSF was shown to be associated with several immune-infiltrating cells and immunomodulators in ccRCC. These results indicated that CTSF might be a promising diagnostic and prognostic marker in ccRCC.
Subject(s)
Carcinoma, Renal Cell , Cathepsin F , Cell Proliferation , Gene Expression Regulation, Neoplastic , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/mortality , Prognosis , Kidney Neoplasms/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/mortality , Female , Male , Cathepsin F/metabolism , Cathepsin F/genetics , Cell Line, Tumor , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Cell Movement/genetics , Middle Aged , Down-RegulationABSTRACT
Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. Aberrant metabolism, a key hallmark of human cancers, plays a crucial role in tumor progression, therapeutic responses and TNBC-related death. However, the underlying mechanisms are not fully understood. In this study, we delineate a previously unrecognized role of aberrant glucose metabolism in regulating the turnover of Snail1, which is a key transcriptional factor of epithelial-mesenchymal transition (EMT) and critically contributes to the acquisition of stemness, metastasis and chemo-resistance. Mechanistically, we demonstrate that AMP-activated protein kinase (AMPK), when activated in response to glucose deprivation, directly phosphorylates Snail1 at Ser11. Such a phosphorylation modification of Snail1 facilitates its recruitment of the E3 ligase FBXO11 and promotes its degradation, thereby suppressing stemness, metastasis and increasing cellular sensitivity to chemotherapies in vitro and in vivo. Clinically, histological analyses reveal a negative correlation between p-AMPKα and Snail1 in TNBC specimens. Taken together, our findings establish a novel mechanism and functional significance of AMPK in linking glucose status to Snail1-dependent malignancies and underscore the potential of AMPK agonists as a promising therapeutic strategy in the management of TNBC.
Subject(s)
AMP-Activated Protein Kinases , Epithelial-Mesenchymal Transition , Snail Family Transcription Factors , Triple Negative Breast Neoplasms , Snail Family Transcription Factors/metabolism , Snail Family Transcription Factors/genetics , Humans , Phosphorylation , AMP-Activated Protein Kinases/metabolism , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/drug therapy , Animals , Female , Cell Line, Tumor , Mice , Glucose/metabolism , Protein Stability , Energy Metabolism/drug effects , Drug Resistance, Neoplasm , F-Box Proteins/metabolism , F-Box Proteins/geneticsABSTRACT
The VHL protein (pVHL) functions as a tumor suppressor by regulating the degradation or activation of protein substrates such as HIF1α and Akt. In human cancers harboring wild-type VHL, the aberrant downregulation of pVHL is frequently detected and critically contributes to tumor progression. However, the underlying mechanism by which the stability of pVHL is deregulated in these cancers remains elusive. Here, we identify cyclin-dependent kinase 1 (CDK1) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) as two previously uncharacterized regulators of pVHL in multiple types of human cancers harboring wild-type VHL including triple-negative breast cancer (TNBC). PIN1 and CDK1 cooperatively modulate the protein turnover of pVHL, thereby conferring tumor growth, chemotherapeutic resistance and metastasis both in vitro and in vivo. Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1. PIN1 then binds to phosphorylated pVHL and facilitates the recruitment of the E3 ligase WSB1, therefore targeting pVHL for ubiquitination and degradation. Furthermore, the genetic ablation or pharmacological inhibition of CDK1 by RO-3306 and PIN1 by all-trans retinoic acid (ATRA), the standard care for Acute Promyelocytic Leukemia could markedly suppress tumor growth, metastasis and sensitize cancer cells to chemotherapeutic drugs in a pVHL dependent manner. The histological analyses show that PIN1 and CDK1 are highly expressed in TNBC samples, which negatively correlate with the expression of pVHL. Taken together, our findings reveal the previous unrecognized tumor-promoting function of CDK1/PIN1 axis through destabilizing pVHL and provide the preclinical evidence that targeting CDK1/PIN1 is an appealing strategy in the treatment of multiple cancers with wild-type VHL.
Subject(s)
CDC2 Protein Kinase , Triple Negative Breast Neoplasms , Humans , NIMA-Interacting Peptidylprolyl Isomerase/genetics , CDC2 Protein Kinase/genetics , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Peptidylprolyl Isomerase/genetics , Peptidylprolyl Isomerase/metabolism , Tretinoin/pharmacologyABSTRACT
Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. TWIST1, a key transcriptional factor of epithelial-mesenchymal transition (EMT), contributes to self-renewal of cancer stem-like cells (CSCs), chemo-resistance, metastasis, and TNBC-related death. However, the mechanism by which TWIST1 is deregulated in TNBC remains elusive. Here, USP29 is identified as a bona fide deubiquitinase of TWIST1. The deubiquitination of TWIST1 catalyzed by USP29 is required for its stabilization and subsequent EMT and CSC functions in TNBC, thereby conferring chemotherapeutic resistance and metastasis. Furthermore, the results unexpectedly reveal that CDK1 functions as the direct USP29 activator. Mechanistically, CDK1-mediated phosphorylation of USP29 is essential for its deubiquitinase activity toward TWIST1 and TWIST1 driven-malignant phenotypes in TNBC, which could be markedly mitigated by the genetic ablation or pharmacological inhibition of CDK1. Moreover, the histological analyses show that CDK1 and USP29 are highly upregulated in TNBC samples, which positively correlate with the expression of TWIST1. Taken together, the findings reveal a previously unrecognized tumor-promoting function and clinical significance of the CDK1-USP29 axis through stabilizing TWIST1 and provide the preclinical evidence that targeting this axis is an appealing therapeutic strategy to conquer chemo-resistance and metastasis in TNBC.
Subject(s)
CDC2 Protein Kinase , Triple Negative Breast Neoplasms , Twist-Related Protein 1 , Ubiquitin-Specific Proteases , Humans , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Deubiquitinating Enzymes , Nuclear Proteins/metabolism , Phosphorylation , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Twist-Related Protein 1/metabolism , Ubiquitin-Specific Proteases/metabolism , Carcinogenesis/geneticsABSTRACT
Breast cancer is one of the most common malignancies in women worldwide. Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype that has the characteristics of easy recurrence, poor prognosis as well as lack of targeted therapeutics. Snail1, a key factor regulating epithelial-mesenchymal transition (EMT) process, contributing to metastasis and chemoresistance in human cancers. However, the molecular mechanism of Snail1 stabilization in cancers is not fully understood. Here, we demonstrate that the deubiquitinating enzyme USP9X deubiquitinates and stabilizes Snail1, thereby promoting metastasis and chemoresistance. The depletion and pharmacological inhibition of USP9X by WP1130, an inhibitor of USP9X, downregulate endogenous Snail1 protein, inhibit cell migration, invasion, metastasis, and increase cellular sensitivity to cisplatin and paclitaxel both in vitro and in vivo, whereas the reconstitution of Snail1 in cells with USP9X depletion at least partially reverses these phenotypes. Overall, our study establishes the USP9X-Snail1 axis as an important regulatory mechanism of breast cancer metastasis and chemoresistance and provides a rationale for potential therapeutic interventions in the treatment of TNBC.
Subject(s)
Drug Resistance, Neoplasm , Neoplasm Metastasis , Snail Family Transcription Factors/metabolism , Triple Negative Breast Neoplasms/drug therapy , Ubiquitin Thiolesterase/metabolism , Cell Line, Tumor , Cell Movement , Deubiquitinating Enzymes/metabolism , Epithelial-Mesenchymal Transition , Female , Humans , Snail Family Transcription Factors/genetics , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolismABSTRACT
Several studies have reported an association between GNß3 C825T polymorphism and irritable bowel syndrome (IBS). However, the results remain inconclusive and controversial, particularly for the data derived from different ethnicities and IBS subtypes. Therefore, we performed an updated meta-analysis to evaluate this association. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and eleven case-control studies were included for detailed evaluation. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the association between GNß3 C825T polymorphism and susceptibility to IBS and its subtypes. Our meta-analysis found no significantly associations of GNß3 C825T polymorphism with IBS risk in all populations. Whereas the C allele was demonstrated to be a decreased risk factor for constipation predominant IBS (IBS-C) in allele model. Additionally, the CC genotype was found to be associated with increased diarrhea predominant IBS (IBS-D) risk in recessive model. Subgroup analysis by ethnicity revealed that these associations held true for the Asian subpopulation. In conclusion, this meta-analysis suggests the C allele of GNß3 C825T might be associated with a decreased risk of IBS-C, and the CC genotype of GNß3 might be associated with increased IBS-D risk.
ABSTRACT
Several studies have reported an association between serotonin receptor type 3 (5-HT3) subunit genes HTR3A (rs1062613) and HTR3E (rs62625044) and diarrhea predominant irritable bowel syndrome (IBS-D). However, the results remain inconclusive and controversial, particularly for the data derived from different ethnicities and genders. Therefore, we performed a meta-analysis to evaluate this association. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and five case-control studies were included for detailed evaluation. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the associations of HTR3A (rs1062613) and HTR3E (rs62625044) polymorphisms with IBS-D risk. Our results revealed statistically significant associations of the HTR3A (rs1062613, C/T) polymorphism with a decreased risk of IBS-D in all genetic models. Additionally, the HTR3E (rs62625044, G/A) polymorphism was also found to be significantly associated with a decreased risk of IBS-D in the allele and recessive models. Subgroup analysis revealed that these associations held true especially for Asians and female. In conclusion, this meta-analysis suggested that the C allele of HTR3A (rs1062613) and the G allele of HTR3E (rs62625044) are associated with a decreased risk of IBS-D.
ABSTRACT
Several recent genome-wide association studies (GWASs) have suggested that the histone deacetylase 9 (HDAC9) gene is associated with stroke, but the reliability of these findings remains controversial, particularly for the data derived from different ethnicities and geographical locations. Therefore, we performed a meta-analysis to explore the associations between HDAC9 polymorphisms and the risk of stroke in the Chinese population. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and six case-control studies with a total of 2,356 stroke patients and 3,420 healthy controls were included. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the associations of 3 HDAC9 gene polymorphisms with stroke risk. Our results revealed statistically significant associations of the rs2107595 (T/C) polymorphism with an increased risk of stroke in the allele, codominant and dominant models. Additionally, the rs2389995 (G/A) polymorphism was found to be significantly associated with a decreased risk of stroke in all genetic models. In conclusion, this meta-analysis suggested that the T allele of rs2107595 in HDAC9 increases the risk of stroke but that the G allele of rs2389995 decreases the risk of stroke in the Chinese population.