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Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer.

ABSTRACT: SMARCA4 and EZH2 are two functional key players of their respective antagonizing chromatin remodeling complexes SWI/SNF and PRC2. EZH2 inhibitory drugs may abrogate pro-oncogenic features of PRC2 and turn the balance to cell differentiation via SWI/SNF activity in cancers. SMARCA4 and EZH2 expression was assessed by RT-PCR in 238 epithelial ovarian cancers (OCs) and put in relation to clinico-pathological parameters and patients' outcome. Optimal thresholds for high and low expression of both variables were calculated by the Youden's index based on receiver operating characteristic (ROC) curves. High SMARCA4 mRNA expression was independently associated with favorable progression-free survival (PFS) (P?=?0.03) and overall survival (OS) (P?=?0.018). As Youden's threshold determination for EZH2 yielded a S-shaped ROC-curve, two cut-off points (29th and 94th percentile) predicting opposite features were defined. Whereas EZH2 mRNA levels beyond the 29th percentile independently predicted poor PFS (P?=?0.034), Cox-regression in EZH2 transcripts above the 94th percentile revealed a conversion from unfavorable to favorable PFS and OS (P?=?0.009 and P?=?0.032, respectively). High SMARCA4 expression associates with improved survival, whereas moderate/high EZH2 expression predicts poor outcome, which converts to favorable survival in ultra-high expressing OCs. This small OC subgroup could be characterized by REV7-abrogated platinum hypersensitivity but concomitant PARP-inhibitor resistance.

SUBMITTER: Leitner K

PROVIDER: S-EPMC7684284 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer.

Leitner Katharina K Tsibulak Irina I Wieser Verena V Knoll Katharina K Reimer Daniel D Marth Christian C Fiegl Heidi H Zeimet Alain G AG

Scientific reports 20201123 1

SMARCA4 and EZH2 are two functional key players of their respective antagonizing chromatin remodeling complexes SWI/SNF and PRC2. EZH2 inhibitory drugs may abrogate pro-oncogenic features of PRC2 and turn the balance to cell differentiation via SWI/SNF activity in cancers. SMARCA4 and EZH2 expression was assessed by RT-PCR in 238 epithelial ovarian cancers (OCs) and put in relation to clinico-pathological parameters and patients' outcome. Optimal thresholds for high and low expression of both va ...[more]

PMID: 33230143

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Project description:BackgroundNational Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat.MethodsPatients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat.ResultsTwenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports.ConclusionsAlthough tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.

Project description:Background:Ovarian cancer has the highest mortality rate among gynecologic cancers, and most patients are diagnosed in advanced stages. Enhancer of zeste homolog 2 (EZH2) is a major tumor marker and an effective therapeutic target for ovarian cancer, but the underlying molecular mechanism remains unclear. The present study investigated the biological effects of EZH2 knockout in SKOV3 cells in vitro and in vivo and explored the molecular mechanism by integrated analysis of messenger RNA sequencing (mRNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data. Methods:The CRISPR/Cas9 system was used to establish EZH2 knockout SKOV3 cells. Protein expression was evaluated by Western blotting. The effect of EZH2 on ovarian cancer was evaluated in vitro with MTT, wound healing, Transwell, and apoptosis assays and in vivo with a xenograft model. mRNA-seq and ChIP-seq were performed to explore the molecular mechanism underlying the biological function of EZH2. Immunohistochemical staining (IHC) of tissue arrays was used to analyze the correlations among EZH2 and CYP27B1 expressions and prognosis. Results:We obtained three EZH2 knockout subclones. EZH2 knockout SKOV3 cells exhibited significantly suppressed proliferation, migration, and invasion and a significantly increased apoptosis rate. The subcutaneous tumor formation rate decreased from 100 to 0% in the EZH2 knockout group. Integrated analysis of the mRNA-seq and ChIP-seq data identified 1,455 significantly upregulated genes with matching downregulated trimethylation of histone H3 lysine 27 (H3K27me3) methylation binding sites in 1b11H cells compared to SKOV3 cells. The set of downregulated genes in EZH2 knockout cells was highly enriched in genes regulating the activation of steroid biosynthesis; the top-ranked hub gene was CYP27B1. The EZH2 and CYP27B1 expression levels showed a statistically significant inverse correlation, which was also associated with unfavorable prognosis. The in vitro experiment demonstrated that CYP27B1 can suppress the proliferation, migration, and invasion of ovarian cancer cells. Moreover, the levels of AKT and p-AKT were significantly increased, whereas STAT3 was downregulated, in 1b11H cells compared to SKOV3 cells. Moreover, STAT3 and AKT overexpression was observed in 1b11H siRNA for CYP27B1 (siCYP27B1) cells. Conclusion:EZH2 plays an important role in promoting cell proliferation, migration, and invasion in ovarian cancer by regulating the core steroid biosynthesis gene via H3K27me3 methylation. Moreover, CYP27B1, the steroid biosynthesis hub gene, might be a novel therapeutic target for ovarian cancer.

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Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer.

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Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer.

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