LINE-1 Retrotransposition Promotes the Development and Progression of Lung Squamous Cell Carcinoma by Disrupting the Tumor-Suppressor Gene FGGY.

Abstract

Somatic long interspersed element-1 (<i>LINE-1</i>) retrotransposition is a genomic process that relates to gene disruption and tumor occurrence. However, the expression and function of <i>LINE-1</i> retrotransposition in lung squamous cell carcinoma (LUSC) remain unclear. We analyzed the transcriptomes of LUSC samples in The Cancer Genome Atlas and observed <i>LINE-1</i> retrotransposition in 90% of tumor samples. Thirteen <i>LINE-1</i> retrotranspositions of high occurrence were identified and further validated from an independent Chinese LUSC cohort. Among them, <i>LINE-1-FGGY</i> (<i>L1-FGGY)</i> was identified as the most frequent <i>LINE-1</i> retrotransposition in the Chinese cohort and significantly correlated with poor clinical outcome. <i>L1-FGGY</i> occurred with smoke-induced hypomethylation of the <i>LINE-1</i> promoter and contributed to the development of local immune evasion and dysfunctional metabolism. Overexpression of <i>L1-FGGY</i> or knockdown of <i>FGGY</i> promoted cell proliferation and invasion <i>in vitro</i>, facilitated tumorigenesis <i>in vivo</i>, and dysregulated cell energy metabolism and cytokine/chemotaxin transcription. Importantly, specific reverse transcription inhibitors, nevirapine and efavirenz, dramatically countered <i>L1-FGGY</i> abundance, inhibited tumor growth, recovered metabolism dysfunction, and improved the local immune evasion. In conclusion, hypomethylation-induced <i>L1-FGGY</i> expression is a frequent genomic event that promotes the development and progression of LUSC and represents a promising predictive biomarker and therapeutic target in LUSC. SIGNIFICANCE: <i>LINE-1-FGGY</i> is a prognosis predictive biomarker and potential therapeutic target to overcome local immune evasion in lung squamous cell carcinoma.