Aberrant epigenetic regulation of FZD3 by TET2 is involved in ovarian cancer cell resistance to cisplatin.

A major challenge in platinum-based cancer therapy, including cisplatin (DDP), is the clinical management of chemo-resistant tumours, which have unknown pathogenesis at the level of epigenetic mechanism. To identify potential resistance mechanisms, we integrated ovarian cancers (OC)-related GEO database retrieval and prognostic analyses. The results of bioinformatics prediction showed that frizzled class receptor 3 (FZD3) was a DDP-associated gene and closely related to the prognosis of OC. DDP resistance in OC inhibited FZD3 expression. FZD3 reduced DDP resistance in OC cells, increased the inhibitory effect of DDP on the growth and aggressiveness of DDP-resistant cells, and promoted apoptosis and DNA damage. TET2 was reduced in OC. TET2 promoted the transcription of FZD3 through DNA hydroxymethylation. TET2 sensitized the drug-resistant cells to DDP in vitro and in vivo, and the ameliorating effect of TET2 on drug resistance was significantly reversed after the inhibition of FZD3. Our findings reveal a previously unknown epigenetic axis TET2/FZD3 suppression as a potential resistance mechanism to DDP in OC.

N6-Methyladenosine-Mediated Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells' Properties and Lenvatinib Resistance Through WNT/ß-Catenin and Hippo Signaling Pathways.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, but there is a deficiency of early diagnosis biomarkers and therapeutic targets. Drug resistance accounts for most HCC-related deaths, yet the mechanisms underlying drug resistance remain poorly understood. METHODS: Expression of Frizzled-10 (FZD10) in liver cancer stem cells (CSCs) was identified by means of RNA sequencing and validated by means of real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of FZD10 on liver CSC expansion and lenvatinib resistance. RNA sequencing, RNA binding protein immunoprecipitation, and luciferase report assays were applied to explore the mechanism underlying FZD10-mediated liver CSCs expansion and lenvatinib resistance. RESULTS: Activation of FZD10 in liver CSCs was mediated by METTL3-dependent N6-methyladenosine methylation of FZD10 messenger RNA. Functional studies revealed that FZD10 promotes self-renewal, tumorigenicity, and metastasis of liver CSCs via activating ß-catenin and YAP1. The FZD10-ß-catenin/YAP1 axis is activated in liver CSCs and predicts poor prognosis. Moreover, FZD10-ß-catenin/c-Jun axis transcriptionally activates METTL3 expression, forming a positive feedback loop. Importantly, the FZD10/ß-catenin/c-Jun/MEK/ERK axis determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort, patient-derived tumor organoids, and patient-derived xenografts further suggest that FZD10 might predict lenvatinib clinical benefit in patients with HCC. Furthermore, treatment of lenvatinib-resistant HCC with adeno-associated virus targeting FZD10 or a ß-catenin inhibitor restored lenvatinib response. CONCLUSIONS: Elevated FZD10 expression promotes expansion of liver CSCs and lenvatinib resistance, indicating that FZD10 expression is a novel prognostic biomarker and therapeutic target for human HCC.

An investigation of bacteriocin nisin anti-cancer effects and FZD7 protein interactions in liver cancer cells.

The bacteriocin, nisin, produced by Lactococcus and Streptococcus species during fermentation, is widely used for bio preservatives in a wide variety of foods. Liver cancer has a high mortality rate and is the fourth leading cause of cancer-related deaths worldwide. Recently, researchers have shown the anti-cancer effects of nisin through in vitro and in vivo studies. This study aimed to investigate the effect of nisin on liver cancer cell lines, which represented two subgroups of the disease model. Nisin exhibited significant growth inhibition and apoptosis in both cell lines, HuH-7, and SNU182. Drug resistance is the main problem in liver cancer and the epithelial-to-mesenchymal transition has a role in the development of drug resistance in hepatocellular carcinoma. The expression of EMT transcription factors ZEB1, SNAI1, and TWIST1 were analyzed depending on nisin treatment, TWIST1 expression was down-regulated after nisin treatment compared to the untreated SNU182 and HuH-7 cell lines. Besides, due to the reported correlation between the overexpression of Frizzled (FZD) proteins, specifically FZD7, in primary hepatocellular carcinomas (HCCs), molecular docking was assessed for Nisin A in the binding site of FZD7. Results confirmed that Nisin A was able to form important hydrogen bonding with key residues. This research not only determined the role of nisin in different liver cancer cell models but it also provided the first result of FZD7 and nisin interaction.

Bioengineered BERA-Wnt5a siRNA Targeting Wnt5a/FZD2 Signaling Suppresses Advanced Prostate Cancer Tumor Growth and Enhances Enzalutamide Treatment.

The next-generation antiandrogen drugs such as enzalutamide and abiraterone extend survival times and improve quality of life in patients with advanced prostate cancer. However, resistance to both drugs occurs frequently through mechanisms that are incompletely understood. Wnt signaling, particularly through Wnt5a, plays vital roles in promoting prostate cancer progression and induction of resistance to enzalutamide and abiraterone. Development of novel strategies targeting Wnt5a to overcome resistance is an urgent need. In this study, we demonstrated that Wnt5a/FZD2-mediated noncanonical Wnt pathway is overexpressed in enzalutamide-resistant prostate cancer. In patient databases, both the levels of Wnt5a and FZD2 expression are upregulated upon the development of enzalutamide resistance and correlate with higher Gleason score, biochemical recurrence, and metastatic status, and with shortened disease-free survival duration. Blocking Wnt5a/FZD2 signal transduction not only diminished the activation of noncanonical Wnt signaling pathway, but also suppressed the constitutively activated androgen receptor (AR) and AR variants. Furthermore, we developed a novel bioengineered BERA-Wnt5a siRNA construct and demonstrated that inhibition of Wnt5a expression by the BERA-Wnt5a siRNA significantly suppressed tumor growth and enhanced enzalutamide treatment in vivo. These results indicate that Wnt5a/FZD2 signal pathway plays a critical role in promoting enzalutamide resistance, and targeting this pathway by BERA-Wnt5a siRNA can be developed as a potential therapy to treat advanced prostate cancer.