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A high-throughput screening platform to identify MYCN expression inhibitors for liver cancer therapy
Yali Xu1,2, Hricha Mishra1, Yutaka Furutani3
1Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences, Kanagawa, Yokohama, Japan.
Abstract:
MYCN, an oncogene implicated in hepatocellular carcinoma (HCC), is predominantly expressed in cancer stem-like HCC cells. It drives tumorigenicity, metastasis, and therapeutic resistance. In this study, we hypothesized that the pharmacological inhibition of MYCN could represent a novel therapeutic strategy for HCC. To identify inhibitors of MYCN expression, we developed an unbiased, high-throughput screening platform. With this platform, we identified MI202 as a potent inhibitor of MYCN expression. MI202 significantly reduced MYCN promoter activity and mRNA levels in HCC cells, inhibiting cell proliferation, spheroid formation, and colony growth and promoting apoptosis. Notably, MI202 selectively inhibited the proliferation of HCC cells but not of normal hepatic cells, highlighting its potential for HCC-specific therapy. Genome-wide CRISPR knockout screening has identified acyl-CoA thioesterase 2 (ACOT2), a key regulator of lipid metabolism, as a molecular target of MI202. ACOT2 downregulation by MI202 was associated with reduced MYCN expression, suggesting that ACOT2 may mediate MYCN-driven tumorigenesis through lipid desaturation. Overall, this study presents a robust high-throughput screening platform to identify MYCN inhibitors and highlights the potential of pharmacological downregulation of MYCN as a therapeutic strategy for targeting HCC.
Insights
Researchers identified MI202, a drug that inhibits the MYCN oncogene, offering a potential new therapy for hepatocellular carcinoma (HCC). This targeted approach reduces cancer cell growth and promotes cell death, sparing normal liver cells.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The MYCN oncogene is crucial in hepatocellular carcinoma (HCC) development, driving tumor growth, metastasis, and resistance to therapy.
- MYCN is highly expressed in cancer stem-like HCC cells, making it a key target for therapeutic intervention.
Purpose of the Study:
- To investigate the potential of pharmacologically inhibiting MYCN as a novel therapeutic strategy for HCC.
- To develop and utilize a high-throughput screening platform for identifying MYCN expression inhibitors.
Main Methods:
- Development of an unbiased, high-throughput screening platform to identify inhibitors of MYCN expression.
- Utilized the platform to identify MI202 as a potent inhibitor of MYCN.
- Performed genome-wide CRISPR knockout screening to identify the molecular target of MI202, which was identified as acyl-CoA thioesterase 2 (ACOT2).
Main Results:
- MI202 significantly reduced MYCN promoter activity and mRNA levels in HCC cells.
- MI202 inhibited HCC cell proliferation, spheroid formation, and colony growth, while promoting apoptosis.
- MI202 demonstrated selective toxicity towards HCC cells, sparing normal hepatic cells, and its action was linked to ACOT2 downregulation.
Conclusions:
- Pharmacological inhibition of MYCN using MI202 represents a promising, targeted therapeutic strategy for HCC.
- The study established a robust screening platform for identifying MYCN inhibitors and identified ACOT2 as a key mediator in MYCN-driven tumorigenesis.
- MI202's selective action on HCC cells highlights its potential for developing HCC-specific therapies.
