Abstract
Recent findings on the existence of oncogenic fusion genes in a wide array of solid tumors, including head and neck squamous cell carcinoma (HNSCC), suggests that fusion genes have become attractive targets for cancer diagnosis and treatment. In this study, we showed for the first time that a read-through fusion gene JMJD7-PLA2G4B is presented in HNSCC, splicing neighboring jumonji domain containing 7 (JMJD7) and phospholipase A2, group IVB (PLA2G4B) genes together. Ablation of JMJD7-PLA2G4B significantly inhibited proliferation of HNSCC cells by promoting G1 cell cycle arrest and increased starvation-induced cell death compared to JMJD7-only knockdown HNSCC cells. Mechanistically, we found that JMJD7-PLA2G4B modulates phosphorylation of Protein Kinase B (AKT) to promote HNSCC cell survival. Moreover, JMJD7-PLA2G4B also regulated an E3 ligase S-phase kinase-associated protein 2 (SKP2) to control the cell cycle progression from G1 phase to S phase by inhibiting Cyclin-dependent kinase inhibitor 1 (p21) and 1B (p27) expression. Our study provides novel insights into the oncogenic control of JMJD7-PLA2G4B in HNSCC cell proliferation and survival, and suggests that JMJD7-PLA2G4B may serve as an important therapeutic target and prognostic marker for HNSCC development and progression.
Highlights
Read-through transcripts are fusion genes resulting from a hybridization of juxtaposed genes from the same chromosome in the same orientation [1,2]
RT-PCR showed that both jumonji domain containing 7 (JMJD7) and JMJD7-PLA2G4B genes were ubiquitously expressed in all head and neck squamous cell carcinoma (HNSCC) cell lines that were examined while PLA2G4B was only detected in few HNSCC cell lines (Figure 1B)
We report for the first time that the read-through fusion gene product JMJD7-PLA2G4B plays a critical role in HNSCC cell proliferation and survival
Summary
Read-through transcripts ( known as conjoined genes) are fusion genes resulting from a hybridization of juxtaposed genes from the same chromosome in the same orientation [1,2]. Fusion genes were first recognized in hematologic malignancies as essential drivers of development and progression of cancer [3,4]. The total number of gene fusions reported in numerous cancers is estimated to be 10,000, where more than 90% of the discoveries occurred in the past 5 years due to recent bioinformatics advancements [4,5]. Studies report that gene fusions occur in all malignancies and account for about 20% of malignant solid tumor morbidity [1]. Thyroid carcinoma was the first epithelial tumor type found to involve a gene fusion, RET-CCDC6, in carcinoma pathogenesis [6, 7]. The relative mechanism by which fusion genes promote the progression of cancer remains largely unknown
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