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Published on: July 17, 2020
Peptide‑based therapeutics targeting the SLC39A14‑PIWIL2 fusion in hepatocellular carcinoma
Masaud Shah1, Sung Ung Moon1, Ji-Hye Choi1,2
1Department of Physiology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
Abstract:
Fusion genes are key oncogenic drivers in various cancers; however, their role in hepatocellular carcinoma (HCC) remains underexplored. Here, we analyzed RNA-seq data from 68 HCC patients and identified several fusion products where SLC39A14-PIWIL2 stood out a putative driver. Functional assays revealed that the promoter of SLC39A14 potentially drives the overexpression of a truncated PIWIL2 protein (tPIWIL2), which retains its oncogenic MID and PIWI domains, in liver tissues. Both the wild-type and tPIWIL2 were found to interact with oncogenic partners HDAC3 and NME2 through these domains, as demonstrated by structural modeling and molecular dynamics simulations. To disrupt these interactions, we designed novel decoy peptides that potentially competes with both HDAC3 and NME2, effectively inhibiting PIWIL2-driven tumor activity in Huh7, HepG2, SNU449, and SNU398 HCC cell lines. Among the tested candidates, NEP1 markedly suppressed PIWIL2-driven oncogenic activity, and its co-administration with 5-fluorouracil (5-FU) significantly reduced PIWIL2-induced chemoresistance, thereby enhancing therapeutic efficacy. Collectively, these findings establish SLC39A14-PIWIL2 as a novel oncogenic fusion in HCC and highlight fusion protein-targeted peptide therapeutics as a promising avenue for precision treatment in HCC.
Insights
Researchers identified a novel fusion gene, SLC39A14-PIWIL2, driving liver cancer (HCC). They developed a peptide therapeutic, NEP1, that inhibits this fusion protein and enhances chemotherapy, offering a new precision treatment for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fusion genes are recognized drivers of various cancers, but their significance in hepatocellular carcinoma (HCC) is not well understood.
- Identifying novel oncogenic drivers is crucial for developing targeted therapies for HCC.
Purpose of the Study:
- To investigate the role of fusion genes in HCC.
- To identify and characterize novel oncogenic fusion proteins in HCC.
- To develop targeted peptide therapeutics against identified fusion proteins for HCC treatment.
Main Methods:
- RNA sequencing analysis of HCC patient samples to identify fusion genes.
- Functional assays to determine the oncogenic role of the SLC39A14-PIWIL2 fusion.
- Structural modeling and molecular dynamics simulations to understand protein interactions.
- In vitro studies using HCC cell lines to test the efficacy of decoy peptides.
- Combination therapy studies with chemotherapy agents.
Main Results:
- The SLC39A14-PIWIL2 fusion gene was identified as a potential driver in HCC, leading to the overexpression of a truncated PIWIL2 protein (tPIWIL2).
- tPIWIL2 interacts with oncogenic partners HDAC3 and NME2.
- A novel decoy peptide, NEP1, effectively inhibited PIWIL2-driven oncogenic activity in HCC cell lines.
- NEP1 enhanced the efficacy of 5-fluorouracil (5-FU) by reducing PIWIL2-induced chemoresistance.
Conclusions:
- SLC39A14-PIWIL2 represents a novel oncogenic fusion in hepatocellular carcinoma.
- Targeted peptide therapeutics against fusion proteins, like NEP1, show promise for precision medicine in HCC.
- Combination therapy with NEP1 and 5-FU offers a potential strategy to improve therapeutic outcomes in HCC.
