A Cell Type-Specific Cryptic Promoter Drives ERVK-7 Overexpression in Lung Cancer
Human endogenous retroviruses have been implicated to play important roles in health and disease, with recent evidence linking ERVK-7 envelope glycoprotein to immune checkpoint blockade response and prognosis in lung adenocarcinoma (LUAD) patients. However, the mechanisms underlying ERVK-7 regulation remain unclear. We show that the 5' long terminal repeat (LTR) of ERVK-7 is methylated and non-functional, requiring alternative upstream promoters to drive its expression via two novel transcripts, ERVK-7.long and ERVK-7.short. ERVK-7.long is the primary driver of ERVK-7 overexpression in LUAD, with the transcript predominantly active in malignant cells. Epigenetic and single-cell RNA analyses reveal that ERVK-7.long activation is predetermined by cellular origin, with tumor necrosis factor-alpha (TNF-alpha) contributing to its upregulation. Higher levels of ERVK-7 observed in LUAD compared with lung squamous cell carcinoma (LUSC) can be further explained by increased interferon signaling, the key regulator of ERVK-7.short, in LUAD. Our findings uncover the mechanistic basis of ERVK-7 upregulation in LUAD and potential avenues for its use as a therapeutic or diagnostic target in non-small cell lung cancer.