Browse
Submit Data
Databases
API
Help

Dataset Information

36 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The USP10-HDAC6 axis confers cisplatin resistance in non-small cell lung cancer lacking wild-type p53.

ABSTRACT: Ubiquitin-specific peptidase 10 (USP10) stabilizes both tumor suppressors and oncogenes in a context-dependent manner. However, the nature of USP10's role in non-small cell lung cancer (NSCLC) remains unclear. By analyzing The Cancer Genome Atlas (TCGA) database, we have shown that high levels of USP10 are associated with poor overall survival in NSCLC with mutant p53, but not with wild-type p53. Consistently, genetic depletion or pharmacological inhibition of USP10 dramatically reduces the growth of lung cancer xenografts lacking wild-type p53 and sensitizes them to cisplatin. Mechanistically, USP10 interacts with, deubiquitinates, and stabilizes oncogenic protein histone deacetylase 6 (HDAC6). Furthermore, reintroducing either USP10 or HDAC6 into a USP10-knockdown NSCLC H1299 cell line with null-p53 renders cisplatin resistance. This result suggests the existence of a "USP10-HDAC6-cisplatin resistance" axis. Clinically, we have found a positive correlation between USP10 and HDAC6 expression in a cohort of NSCLC patient samples. Moreover, we have shown that high levels of USP10 mRNA correlate with poor overall survival in a cohort of advanced NSCLC patients who received platinum-based chemotherapy. Overall, our studies suggest that USP10 could be a potential biomarker for predicting patient response to platinum, and that targeting USP10 could sensitize lung cancer patients lacking wild-type p53 to platinum-based therapy.

SUBMITTER: Hu C

PROVIDER: S-EPMC7206099 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis.

Project description:TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant.

| S-EPMC4670040 | biostudies-literature

Depletion of HDAC6 enhances cisplatin-induced DNA damage and apoptosis in non-small cell lung cancer cells.

Project description:Histone deacetylase inhibitors (HDACi) are promising therapeutic agents which are currently used in combination with chemotherapeutic agents in clinical trials for cancer treatment including non-small cell lung cancer (NSCLC). However, the mechanisms underlying their anti-tumor activities remain elusive. Previous studies showed that inhibition of HDAC6 induces DNA damage and sensitizes transformed cells to anti-tumor agents such as etoposide and doxorubicin. Here, we showed that depletion of HDAC6 in two NSCLC cell lines, H292 and A549, sensitized cells to cisplatin, one of the first-line chemotherapeutic agents used to treat NSCLC. We suggested that depletion of HDAC6 increased cisplatin-induced cytotoxicity was due to the enhancement of apoptosis via activating ATR/Chk1 pathway. Furthermore, we showed that HDAC6 protein levels were positively correlated with cisplatin IC(50) in 15 NSCLC cell lines. Lastly, depletion of HDAC6 in H292 xenografts rendered decreased tumor weight and volume and exhibited increased basal apoptosis compared with the controls in a xenograft mouse model. In summary, our findings suggest that HDAC6 is positively associated with cisplatin resistance in NSCLC and reveal HDAC6 as a potential novel therapeutic target for platinum refractory NSCLC.

| S-EPMC3434198 | biostudies-literature

Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells.

Project description:Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necroptosis-related regulator MLKL in human NSCLC tissues and cell lines. Knockdown of Skp2 inhibited viability, anchorage-independent growth, and in vivo tumor development of NSCLC cells. We also found that the Skp2 protein is negatively correlated with MLKL in NSCLC tissues. Moreover, Skp2 is increased and accompanied by an upregulation of MLKL ubiquitination and degradation in cisplatin-resistant NSCLC cells. Accordingly, inhibition of Skp2 partially restores MLKL and sensitizes NSCLC cells to cisplatin in vitro and in vivo. Mechanistically, Skp2 interacts and promotes ubiquitination-mediated degradation of MLKL in cisplatin-resistant NSCLC cells. Our results provide evidence of an Skp2-dependent mechanism regulating MLKL degradation and cisplatin resistance, suggesting that targeting Skp2-ubiquitinated MLKL degradation may overcome NSCLC chemoresistance.

| S-EPMC10397346 | biostudies-literature

FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer.

Project description:Lung cancer is one of the leading causes of cancer mortality worldwide. The therapeutic effect of chemotherapy is limited due to the resistance of cancer cells, which remains a challenge in cancer therapeutics. In this work, we found that flap endonuclease 1 (FEN1) is overexpressed in lung cancer cells. FEN1 is a major component of the base excision repair pathway for DNA repair systems and plays important roles in maintaining genomic stability through DNA replication and repair. We showed that FEN1 is critical for the rapid proliferation of lung cancer cells. Suppression of FEN1 resulted in decreased DNA replication and accumulation of DNA damage, which subsequently induced apoptosis. Manipulating the amount of FEN1 altered the response of lung cancer cells to chemotherapeutic drugs. A small-molecule inhibitor (C20) was used to target FEN1 and this enhanced the therapeutic effect of cisplatin. The FEN1 inhibitor significantly suppressed cell proliferation and induced DNA damage in lung cancer cells. In mouse models, the FEN1 inhibitor sensitized lung cancer cells to a DNA damage-inducing agent and efficiently suppressed cancer progression in combination with cisplatin treatment. Our study suggests that targeting FEN1 may be a novel and efficient strategy for a tumor-targeting therapy for lung cancer.

| S-EPMC5467497 | biostudies-literature

Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2.

Project description:Nrf2 is a key transcription factor for genes coding for antioxidants, detoxification enzymes, and multiple drug resistance and it also confers resistance to anticancer drugs. Here, we hypothesized that mutant p53 could upregulate Nrf2 expression at the transcriptional level, thereby conferring cisplatin resistance in non-small cell lung cancer (NSCLC). Luciferase reporter assays and real-time PCR analysis indicated that the Nrf2 promoter activity and its mRNA levels were markedly suppressed by wild-type p53, but not by mutant p53. Chromatin immunoprecipitation (ChIP) further confirmed that wild-type p53 binds at the p53 putative binding site to block Sp1 binding to the Nrf2 promoter and consequently to suppress the Nrf2 promoter activity. The MTT assay indicated that an increase in Nrf2 expression by mutant p53 is responsible for cisplatin resistance. Among the Nrf2 downstream genes, Bcl-2 and Bcl-xL contribute more strongly to Nrf2-mediated cisplatin resistance when compared with heme oxygenase 1 (HO-1). Cox regression analysis showed that patients with high-Nrf2, high-Bcl-2, high-Bcl-xL mRNA tumors were more commonly occurred unfavorable response to cisplatin-based chemotherapy than their counterparts. The prognostic significance of Nrf2 mRNA levels on OS and RFS was also observed in patients who have received cisplatin-based chemotherapy, particularly in p53-mutant patients. Collectively, mutant p53 may confer cisplatin resistance via upregulation of Nrf2 expression, and Nrf2 mRNA level may predict chemotherapeutic response and outcomes in NSCLC.

| S-EPMC4747182 | biostudies-literature

USP10 regulates p53 localization and stability by deubiquitinating p53.

Project description:Stability and localization of p53 is essential for its tumor suppressor function. Ubiquitination by the E3 ubiquitin ligase Mdm2 is the major regulatory mechanism of p53, which induces p53 nuclear export and degradation. However, it is unclear whether ubiquitinated cytoplasmic p53 can be recycled. Here, we report that USP10, a cytoplasmic ubiquitin-specific protease, deubiquitinates p53, reversing Mdm2-induced p53 nuclear export and degradation. After DNA damage, USP10 is stabilized, and a fraction of USP10 translocates to the nucleus to activate p53. The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337. Finally, USP10 suppresses tumor cell growth in cells with wild-type p53, with USP10 expression downregulated in a high percentage of clear cell carcinomas, known to have few p53 mutations. These findings reveal USP10 to be a novel regulator of p53, providing an alternative mechanism of p53 inhibition in cancers with wild-type p53.

| S-EPMC2820153 | biostudies-literature

Scriptaid overcomes hypoxia-induced cisplatin resistance in both wild-type and mutant p53 lung cancer cells.

Project description:Non-small cell lung cancer (NSCLC), comprising 85% of lung cancer cases, has been associated with resistance to chemo/radiotherapy. The hypoxic tumor micro-environment, where insufficient vasculature results in poor drug penetrance and sub-optimal chemotherapy in the tumor interiors contributes heavily to this resistance. Additionally, epigenetic changes in tumorigenic cells also change their response to different forms of therapy. In our study, we have investigated the effectiveness of a combination of cisplatin with scriptaid [a pan-Histone Deacetylase inhibitor (HDACi)] in a model that mimics the tumor microenvironment of hypoxia and sub-lethal chemotherapy. Scriptaid synergistically increases the efficacy of cisplatin in normoxia as well as hypoxia, accompanied with reduced metastasis and enhanced DNA damage. Addition of scriptaid also overcomes the cisplatin resistance exhibited in lung cancer cells with stabilized hypoxia inducible factor 1 (HIF1)-α (mutant) and mutant p53. Molecular studies showed that the combination treatment increased apoptotic cell death in both normoxia and hypoxia with a dual role of p38MAPK. Together, our results suggest that the combination of low dose cisplatin and scriptaid is cytotoxic to NSCLC lines, can overcome hypoxia induced resistance and mutant p53- induced instability often associated with this cancer, and has the potential to be an effective therapeutic modality.

| S-EPMC5342127 | biostudies-literature

WP1130 attenuates cisplatin resistance by decreasing P53 expression in non-small cell lung carcinomas.

Project description:Cisplatin-based combination chemotherapy significantly improves the survival outcomes in non-small cell lung carcinomas (NSCLCs), but drug resistance commonly contributes to disease progression and relapse. Recently, accumulating evidence has indicated that deubiquitinases (DUBs) are involved in regulating tumor cell proliferation, apoptosis, and chemoresistance. We designed this study to investigate the role of WP1130, a DUB inhibitor, in regulating cisplatin cytotoxicity in NSCLCs. After being combined with WP1130, cisplatin sensitivity was significantly increased in A549 and HCC827 cells with decreased p53 expression, inhibiting their proliferation, but not in p53-deficient NCI-H1299 cells. The synergistic cytotoxicity of the cisplatin and WP1130 co-treatment was abolished in p53-knockdown cells. Western blotting verified the decreased p53 expression in A549 and HCC827 cells treated with cisplatin and WP1130. The administration of MG132, a proteasome inhibitor, or knockdown of ubiquitin-specific peptidase 9, X-linked (USP9X) both eliminated the effect of WP1130 in decreasing p53 expression. Taken together, our findings confirm that the inclusion of WP1130 is potentially contributes to better therapeutic effects of cisplatin-based chemotherapy of NSCLCs in a manner dependent on the USP9X-p53 ubiquitination-mediated degradation pathway.

| S-EPMC5564746 | biostudies-literature

Shp2 confers cisplatin resistance in small cell lung cancer via an AKT-mediated increase in CA916798.

Project description:The tyrosine phosphatase Shp2 is associated with tumorigenesis in small cell lung cancer (SCLC). However, the relationship between Shp2 and resistance to chemotherapy remains unclear. Here, we show that Shp2 plays an important role in inducing resistance to cisplatin-based chemotherapy via the SHP2-AKT-CA916798 pathway. In an SCLC cell line, overexpression of Shp2 induced cisplatin resistance and the increased expression of AKT, pAKT, pmTOR, and CA916798. Conversely, depletion of Shp2 in a cisplatin-resistant cell line via RNA interference increased cisplatin sensitivity and decreased AKT, pAKT, pmTOR, and CA916798 expression levels. Activation of AKT stimulated CA916798 expression and altered the level of Shp2. A mouse xenograft model verified the results obtained from the in vitro experiments. In addition, we collected and analyzed clinical SCLC specimens and found that Shp2 levels correlated with CA916798 expression in tumor tissues. Importantly, higher levels of Shp2 or CA916798 were associated with a poorer prognosis in SCLC patients who received chemotherapy. Together, our findings indicate that Shp2 induces cisplatin resistance in SCLC patients via the SHP2-AKT-CA916798 pathway. Therefore, Shp2 and CA916798 may be promising biomarkers for predicting resistance to chemotherapy and may function as targets for enhancing treatments.

| S-EPMC5410335 | biostudies-literature

LncRNA HOXA-AS3 confers cisplatin resistance by interacting with HOXA3 in non-small-cell lung carcinoma cells.

Project description:Many studies have indicated that the aberrant expression of long noncoding RNAs (lncRNAs) is responsible for drug resistance, which represents a substantial obstacle for cancer therapy. In the present study, we aimed to investigate the role of the lncRNA HOXA-AS3 in drug resistance and elucidate its underlying mechanisms in non-small-cell lung carcinoma (NSCLC) cells. The role of HOXA-AS3 in drug resistance was demonstrated by the cell counting kit-8 assay (CCK-8), ethynyldeoxyuridine (EDU) assay, and flow cytometry analysis. Tumor xenografts in nude mice were established to evaluate the antitumor effects of HOXA-AS3 knockdown in vivo. Western blotting and quantitative real-time PCR were used to evaluate protein and RNA expression. RNA pull-down assays, mass spectrometry, and RNA immunoprecipitation were performed to confirm the molecular mechanism of HOXA-AS3 in the cisplatin resistance of NSCLC cells. We found that HOXA-AS3 levels increased with cisplatin treatment and knockdown of HOXA-AS3 enhance the efficacy of cisplatin in vitro and in vivo. Mechanistic investigations showed that HOXA-AS3 conferred cisplatin resistance by down-regulating homeobox A3 (HOXA3) expression. Moreover, HOXA-AS3 was demonstrated to interact with both the mRNA and protein forms of HOXA3. In addition, HOXA3 knockdown increased cisplatin resistance and induced epithelial-mesenchymal transition (EMT). Taken together, our findings suggested that additional research into HOXA-AS3 might provide a better understanding of the mechanisms of drug resistance and promote the development of a novel and efficient strategy to treat NSCLC.

| S-EPMC6794325 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data