A novel cancer-germline gene DAZL promotes progression and cisplatin resistance of non- small cell lung cancer by upregulating JAK2 and MCM8

Abstract

Abstract Background Germline-specific genes are usually activated in cancer cells and drive cancer progression; such genes are called cancer-germline or cancer-testis genes. Deleted in azoospermia-like (DAZL) is a germline-specific gene whose role in gametogenesis is well characterized, but whose expression and function in non-small cell lung cancer (NSCLC) is unknown. Methods RNA-seq data from Genotype Tissue Expression and The Cancer Genome Atlas were used to analyze DAZL mRNA levels. An immunochemical assay was performed to detect DAZL protein levels in a lung tissue microarray. Cell viability, EdU staining, colony formation, wound healing, and invasion assays were performed for in vitro functional analysis. The in vivo effect of DAZL on tumor growth was investigated using a subcutaneous murine xenograft model. Quantitative proteomics was performed to explore the potential targets of DAZL. Results DAZL was exclusively expressed in testis among normal human tissues but ectopically expressed in NSCLC tissues. Testis and NSCLC cells expressed the shorter and longer transcript variants of the DAZL gene, respectively. Overexpression of the longer DAZL transcript promoted tumor growth in a murine xenograft model. Silencing DAZL suppressed viability, colony formation, migration, and invasion of NSCLC cells. Mechanistically, DAZL binds to the mRNAs of Janus kinase 2 (JAK2) and minichromosome maintenance 8 (MCM8) to upregulate their translation. The JAK2 inhibitor fedratinib attenuated the effects of DAZL overexpression on cell viability, colony formation, migration, and invasion, while silencing MCM8 counteracted the effects of DAZL overexpression on cisplatin-damaged DNA synthesis and the half-maximal inhibitory concentration of cisplatin in NSCLC cells. Conclusion DAZL was identified as a novel cancer-germline gene that enhances translation of JAK2 and MCM8 to promote NSCLC progression and cisplatin resistance, respectively. These results suggest that DAZL is a potential therapeutic target in NSCLC.