Ubiquitin ligase TRIM71 suppresses ovarian tumorigenesis by degrading mutant p53

Abstract Hotspot p53 mutants augment cancer cell proliferation, metastasis and metabolism through their gain-of-function (GOF). Ovarian cancer sustains the highest frequency of TP53 mutations, but the mechanisms underlying regulation of mutant p53s’ GOF in this type of cancer remain incompletely understood. Herein, we identified the E3-ubiquitin ligase TRIM71 as a novel mutant p53-binding protein. Ectopic TRIM71-induced ubiquitination and proteasomal degradation of mutant p53 by binding to its transactivation (TA) domain, and inhibited the expression of a broad spectrum of mutant p53 target genes. Ectopic TRIM71 also restrained, whereas ablation of TRIM71 endorsed, ovarian carcinoma cell growth in vitro and in vivo. Significantly, TRIM71 overexpression is highly associated with favorable prognosis, particularly, in TP53-mutated ovarian carcinomas. Altogether, our findings unveil the anti-tumor function of TRIM71 in ovarian cancer development and prognosis by downregulating mutant p53s.

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BCL7C suppresses ovarian cancer growth by inactivating mutant p53

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjaa065 ◽

2020 ◽

Author(s):

Canhua Huang ◽

Qian Hao ◽

Getao Shi ◽

Xiang Zhou ◽

Yu Zhang

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Target Genes ◽

Ovarian Cancer Cells ◽

Mutant P53 ◽

Ovarian Carcinomas ◽

Ovarian Tumorigenesis ◽

P53 Target Genes ◽

Proliferation And Invasion

Abstract B-cell CLL/lymphoma 7 protein family member C (BCL7C) located at chromosome 16p11.2 shares partial sequence homology with the other two family members, BCL7A and BCL7B. Its role in cancer remains completely unknown. Here, we report our finding of its tumor-suppressive role in ovarian cancer. Supporting this is that BCL7C is downregulated in human ovarian carcinomas, and its underexpression is associated with unfavorable prognosis of ovarian cancer as well as some other types of human cancers. Also, ectopic BCL7C restrains cell proliferation and invasion of ovarian cancer cells. Consistently, depletion of BCL7C reduces apoptosis and promotes cell proliferation and invasion of these cancer cells. Mechanistically, BCL7C suppresses mutant p53-mediated gene transcription by binding to mutant p53, while knockdown of BCL7C enhances the expression of mutant p53 target genes in ovarian cancer cells. Primary ovarian carcinomas that sustain low levels of BCL7C often show the elevated expression of mutant p53 target genes. In line with these results, BCL7C abrogates mutant p53-induced cell proliferation and invasion, but had no impact on proliferation and invasion of cancer cells with depleted p53 or harboring wild-type p53. Altogether, our results demonstrate that BCL7C can act as a tumor suppressor to prevent ovarian tumorigenesis and progression by counteracting mutant p53 activity.

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ASPP1 and ASPP2: Common Activators of p53 Family Members

Molecular and Cellular Biology ◽

10.1128/mcb.24.3.1341-1350.2004 ◽

2004 ◽

Vol 24 (3) ◽

pp. 1341-1350 ◽

Cited By ~ 163

Author(s):

Daniele Bergamaschi ◽

Yardena Samuels ◽

Boquan Jin ◽

Sai Duraisingham ◽

Tim Crook ◽

...

Keyword(s):

Rna Interference ◽

Tumor Growth ◽

Target Genes ◽

Family Members ◽

Mutant P53 ◽

P53 Family ◽

P53 Target Genes

ABSTRACT We recently showed that ASPP1 and ASPP2 stimulate the apoptotic function of p53. We show here that ASPP1 and ASPP2 also induce apoptosis independently of p53. By binding to p63 and p73 in vitro and in vivo, ASPP1 and ASPP2 stimulate the transactivation function of p63 and p73 on the promoters of Bax, PIG3, and PUMA but not mdm2 or p21WAF-1/CIP1. The expression of ASPP1 and ASPP2 also enhances the apoptotic function of p63 and p73 by selectively inducing the expression of endogenous p53 target genes, such as PIG3 and PUMA, but not mdm2 or p21WAF-1/CIP1. Removal of endogenous p63 or p73 with RNA interference demonstrated that (16) the p53-independent apoptotic function of ASPP1 and ASPP2 is mediated mainly by p63 and p73. Hence, ASPP1 and ASPP2 are the first two identified common activators of all p53 family members. All these results suggest that ASPP1 and ASPP2 could suppress tumor growth even in tumors expressing mutant p53.

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Maximal killing of lymphoma cells by DNA damage–inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim

Blood ◽

10.1182/blood-2010-04-280818 ◽

2010 ◽

Vol 116 (24) ◽

pp. 5256-5267 ◽

Cited By ~ 65

Author(s):

Lina Happo ◽

Mark S. Cragg ◽

Belinda Phipson ◽

Jon M. Haga ◽

Elisa S. Jansen ◽

...

Keyword(s):

Dna Damage ◽

Drug Resistance ◽

Target Genes ◽

B Cell Lymphoma ◽

Chemotherapeutic Agents ◽

Lymphoid Cells ◽

Lymphoma Cells ◽

P53 Target Genes

Abstract DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eμ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eμ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eμ-Myc/Puma−/−Noxa−/− lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa−/−Puma−/−Bim−/− mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.

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Aspirin inhibits tumor progression and enhances cisplatin sensitivity in epithelial ovarian cancer

PeerJ ◽

10.7717/peerj.11591 ◽

2021 ◽

Vol 9 ◽

pp. e11591

Author(s):

Jianfeng Guo ◽

Yapei Zhu ◽

Lili Yu ◽

Yuan Li ◽

Jing Guo ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Growth Inhibition ◽

Epithelial Ovarian Cancer ◽

Target Genes ◽

Tumor Growth Inhibition ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

P53 Target Genes

Background Ovarian cancer is the most common gynecological malignancy and is difficult to manage due to the emergence of resistance to various chemotherapeutic drugs. New efforts are urgently awaited. Aspirin, which is traditionally considered a nonsteroidal anti-inflammatory drug (NSAID), has been reported to exert potential chemopreventive effects. Therefore, we aimed to investigate the anticancer effect and explore the underlying molecular mechanisms of aspirin on epithelial ovarian cancer (EOC) cells. Methods We conducted wound healing, transwell migration, EdU cell proliferation, colony formation and apoptosis detection assays to observe the effects of aspirin on the migration, proliferation and apoptosis of EOC cells (A2870, Caov-3, and SK-OV-3). EOC cells were treated with a combination of aspirin and cisplatin (CDDP) to observe the effect of aspirin on enhancing CDDP sensitivity. Orthotopic xenograft models of ovarian cancer established with A2780-Luciferase-GFP cells were applied to compare tumor growth inhibition in the control, CDDP and CDDP plus aspirin groups through in vivo imaging, which can be used to continuously monitor tumor growth. The expression and acetylation levels of p53 in EOC cells treated with aspirin were determined using western blotting, and p53 acetylation levels were examined in tumors harvested from the transplanted mice. Quantitative real-time PCR was used to assess the mRNA expression of p53 target genes. Results Aspirin inhibited migration and proliferation and induced apoptosis in EOC cell lines in a concentration-dependent manner. In vitro, aspirin enhanced the sensitivity of EOC cells to CDDP by increasing its inhibitory effect on proliferation and its effect on inducing apoptosis. In vivo, the differences in the tumor growth inhibition rates among the different CDDP experimental groups were statistically significant (p < 0.05). Aspirin did not affect p53 protein expression but increased the p53 acetylation level in a concentration-dependent manner. In addition, the mRNA levels of CDKN1A, BAX, FOXF1, PUMA, and RRAD in EOC cells were significantly increased by the aspirin treatment. Conclusions Aspirin inhibits tumor progression and enhances the CDDP sensitivity of EOC cells. These antitumor effects of aspirin might be mediated by p53 acetylation and subsequent activation of p53 target genes.

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Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness

Molecular Cancer ◽

10.1186/s12943-020-1130-z ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 7

Author(s):

Sandra Muñoz-Galván ◽

Blanca Felipe-Abrio ◽

Eva M. Verdugo-Sivianes ◽

Marco Perez ◽

Manuel P. Jiménez-García ◽

...

Keyword(s):

Ovarian Cancer ◽

Molecular Mechanisms ◽

Target Genes ◽

Hippo Pathway ◽

Ovarian Tumors ◽

Tumor Resistance ◽

Functional Link ◽

The Hippo Pathway

Abstract Background Ovarian cancer is one of the most common and malignant cancers, partly due to its late diagnosis and high recurrence. Chemotherapy resistance has been linked to poor prognosis and is believed to be linked to the cancer stem cell (CSC) pool. Therefore, elucidating the molecular mechanisms mediating therapy resistance is essential to finding new targets for therapy-resistant tumors. Methods shRNA depletion of MYPT1 in ovarian cancer cell lines, miRNA overexpression, RT-qPCR analysis, patient tumor samples, cell line- and tumorsphere-derived xenografts, in vitro and in vivo treatments, analysis of data from ovarian tumors in public transcriptomic patient databases and in-house patient cohorts. Results We show that MYPT1 (PPP1R12A), encoding myosin phosphatase target subunit 1, is downregulated in ovarian tumors, leading to reduced survival and increased tumorigenesis, as well as resistance to platinum-based therapy. Similarly, overexpression of miR-30b targeting MYPT1 results in enhanced CSC-like properties in ovarian tumor cells and is connected to the activation of the Hippo pathway. Inhibition of the Hippo pathway transcriptional co-activator YAP suppresses the resistance to platinum-based therapy induced by either low MYPT1 expression or miR-30b overexpression, both in vitro and in vivo. Conclusions Our work provides a functional link between the resistance to chemotherapy in ovarian tumors and the increase in the CSC pool that results from the activation of the Hippo pathway target genes upon MYPT1 downregulation. Combination therapy with cisplatin and YAP inhibitors suppresses MYPT1-induced resistance, demonstrating the possibility of using this treatment in patients with low MYPT1 expression, who are likely to be resistant to platinum-based therapy.

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Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers

Cancers ◽

10.3390/cancers13235908 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5908

Author(s):

Adam Neal ◽

Tiffany Lai ◽

Tanya Singh ◽

Neela Rahseparian ◽

Tristan Grogan ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Synergistic Effects ◽

Ovarian Cancer Cells ◽

High Grade ◽

Ovarian Carcinomas ◽

Ovarian Cancer Cell Lines ◽

Poor Outcomes

Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.

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PAX8 orchestrates an angiogenic program through interaction with SOX17

10.1101/2020.09.09.290387 ◽

2020 ◽

Author(s):

Daniele Chaves-Moreira ◽

Marilyn A. Mitchell ◽

Cristina Arruza ◽

Priyanka Rawat ◽

Simone Sidoli ◽

...

Keyword(s):

Ovarian Cancer ◽

Therapeutic Target ◽

Ovarian Carcinomas ◽

Molecular Feature ◽

Current Therapies ◽

Bona Fide ◽

The Impact

ABSTRACTWorldwide, the number of new ovarian cancer cases approaches 300,000 with more than 180,000 deaths every year. The low survival-rate reflects the limitations of current therapies and highlights the importance of identifying new therapeutic targets. Despite significant recent efforts to identify novel vulnerabilities in ovarian cancer, none have led to effective durable therapies with improvement in overall survival. PAX8, a lineage-transcription factor, whose expression is a major molecular feature of ovarian carcinomas, represents a novel therapeutic target. Herein, we have identified SOX17 as a bona fide PAX8-interacting partner and elucidated the impact of this interaction on the development of ovarian cancer. Importantly, we found that PAX8 and SOX17 regulate tumor angiogenesis in vitro and in vivo. The role of PAX8 and SOX17 in the regulation of angiogenesis reveals a novel function for these factors in regulating the tumor microenvironment and highlight this pathway as a viable therapeutic target.

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LDLR-mediated lipidome–transcriptome reprogramming in cisplatin insensitivity

Endocrine Related Cancer ◽

10.1530/erc-19-0095 ◽

2020 ◽

Vol 27 (2) ◽

pp. 81-95 ◽

Cited By ~ 3

Author(s):

Wei-Chun Chang ◽

Hsiao-Ching Wang ◽

Wei-Chung Cheng ◽

Juan-Cheng Yang ◽

Wei-Min Chung ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Density Lipoprotein ◽

Lipoprotein Receptor ◽

Ovarian Carcinomas ◽

Platinum Based Chemotherapy ◽

Cisplatin Sensitivity

Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptor-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularities, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients’ disease prognosis. In vitro and in vivo add-in/silencing LDLR was introduced to determine cisplatin sensitivity and cancer growth. Results revealed that knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR→LPC (Lyso-phosphatidylcholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR→LPC→FAM83B→FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs. Significance: this study describes the role of LDLR in the development of insensitivity to platinum-based chemotherapy in epithelial ovarian cancer. The lipidome (e.g., LPC) and transcriptome (e.g., FAM38B) interactions revealed using trans-omics approaches an LDLR→LPC→FAM83B→FGFRs regulatory axis in cancer cells, in an animal model, and in patients.

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Mucins and Truncated O-Glycans Unveil Phenotypic Discrepancies between Serous Ovarian Cancer Cell Lines and Primary Tumours

International Journal of Molecular Sciences ◽

10.3390/ijms19072045 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2045 ◽

Cited By ~ 4

Author(s):

Ricardo Coelho ◽

Lara Marcos-Silva ◽

Nuno Mendes ◽

Daniela Pereira ◽

Catarina Brito ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Expression Profiles ◽

Ovarian Carcinomas ◽

Cellular Models ◽

Ovarian Cancer Cell Lines ◽

Ovca Cell

Optimal research results rely on the selection of cellular models capable of recapitulating the characteristics of primary tumours from which they originate. The expression of mucins (MUC16 and MUC1) and truncated O-glycans (Tn, STn and T) represents a characteristic footprint of serous ovarian carcinomas (SOCs). Therefore, selecting ovarian cancer (OVCA) cell lines that reflect this phenotype is crucial to explore the putative biological role of these biomarkers in the SOC setting. Here, we investigated a panel of OVCA cell lines commonly used as SOC models, and tested whether, when cultured in 2D and 3D conditions, these recapitulate the mucin and O-glycan expression profiles of SOCs. We further explored the role of truncating the O-glycosylation capacity in OVCAR3 cells through knockout of the COSMC chaperone, using in vitro and in vivo assays. We found that the majority of OVCA cell lines of serous origin do not share the mucin and truncated O-glycan footprint of SOCs, although 3D cultures showed a higher resemblance. We also found that genetic truncation of the O-glycosylation capacity of OVCAR3 cells did not enhance oncogenic features either in vitro or in vivo. This study underscores the importance of well-characterized cellular models to study specific features of ovarian cancer.

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