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Six-methoxyflavone suppresses CircPIAS1 biogenesis via targeting PTBP1 and, in combination with IFN-γ, promotes
Yong-Qi Guo1,2, Xi Wu1, Xin Zang1
1Basic Medical Research Innovation Center for Anti-Cancer Drugs, MOE and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Background/Objectives:
Melanoma remains a highly aggressive malignancy with limited therapeutic options targeting its underlying pathogenesis. CircPIAS1 (circbase ID: hsa_circ_0008378) and its encoded protein circPIAS1-108aa contribute to tumor progression by suppressing STAT1 phosphorylation and immunogenic ferroptosis, yet specific pharmacological agents of directly targeting circPIAS1 are lacking. This study aimed to identify natural products that selectively inhibit circPIAS1 biogenesis, there-by exploring novel therapeutic strategies for melanoma.
Methods:
A library of 128 anticancer natural products was screened using qRT-PCR to identify metabolites selectively suppressing circPIAS1, with 6-methoxyflavone (6-MF) selected. CCK-8 assay determined 6-MF's IC50 for inhibiting melanoma cell proliferation. RNA sequencing and western blot analyzed the PI3K-AKT pathway, STAT1 phosphorylation, SLC7A11/GPX4 signaling pathway, and circPIAS1-108aa. EdU and lipid ROS assays evaluated cell proliferation and oxidative response. RBPmap database identified PTBP1 as a key RNA-binding protein (RBP) in circPIAS1 biogenesis, validated via dose/time-dependent 6-MF treatments and siRNA experiments. A subcutaneous tumor model was used to evaluate the effects of 6-MF, a PD-1 inhibitor, and their combination.
Results:
6-MF was identified as a selective suppressor of circPIAS1 without affecting its host PIAS1 gene. Mechanistically, 6-MF inhibited PTBP1 (critical for circPIAS1 biogenesis) in a dose- and time-dependent manner, reducing circPIAS1-108aa expression. It suppressed the PI3K-AKT pathway,and when combined with IFN-γ, it significantly enhanced STAT1 phosphorylation, and downregulated SLC7A11/GPX4, increasing lipid ROS and promoting ferroptosis. In vivo, 6-MF combined with PD-1 inhibitor synergistically inhibited melanoma growth.
Conclusion:
6-MF targets PTBP1 to inhibit circPIAS1 biogenesis and reduce circPIAS1-108aa.6-MF inhibits PI3K-AKT pathway; combined with IFN-γ, it enhances STAT1 phosphorylation, inhibits SLC7A11/GPX4 pathway, promoting melanoma ferroptosis. Its combination with PD-1 inhibitor enhances antitumor efficacy, providing a novel therapeutic strategy for melanoma treatment.
Insights
6-methoxyflavone (6-MF) inhibits melanoma progression by targeting circPIAS1 biogenesis via PTBP1. This natural product promotes ferroptosis and enhances antitumor efficacy when combined with PD-1 inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Melanoma is an aggressive cancer with few targeted therapies.
- CircPIAS1 and its protein circPIAS1-108aa promote melanoma by suppressing STAT1 phosphorylation and ferroptosis.
- Targeting circPIAS1 is a potential therapeutic strategy, but specific inhibitors are lacking.
Purpose of the Study:
- To screen for natural products that selectively inhibit circPIAS1 biogenesis.
- To explore novel therapeutic strategies for melanoma based on circPIAS1 inhibition.
Main Methods:
- Screened 128 natural products for circPIAS1 suppression using qRT-PCR, identifying 6-methoxyflavone (6-MF).
- Assessed 6-MF's effects on cell proliferation, PI3K-AKT pathway, STAT1 phosphorylation, and ferroptosis markers (SLC7A11/GPX4, lipid ROS).
- Validated PTBP1 as a key RNA-binding protein in circPIAS1 biogenesis and evaluated 6-MF in a melanoma xenograft model.
Main Results:
- 6-MF selectively inhibited circPIAS1 biogenesis by targeting PTBP1, reducing circPIAS1-108aa expression without affecting the PIAS1 gene.
- 6-MF suppressed the PI3K-AKT pathway and, with IFN-γ, enhanced STAT1 phosphorylation and promoted ferroptosis by downregulating SLC7A11/GPX4.
- Combination therapy of 6-MF and a PD-1 inhibitor synergistically inhibited melanoma tumor growth in vivo.
Conclusions:
- 6-MF is a novel inhibitor of circPIAS1 biogenesis targeting PTBP1, offering a new approach to melanoma treatment.
- 6-MF modulates key signaling pathways (PI3K-AKT, STAT1) and induces ferroptosis, enhancing antitumor efficacy.
- Combined 6-MF and PD-1 inhibitor therapy shows significant potential for treating melanoma.
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