TY - JOUR
T1 - LINE-1 retrotransposition promotes the development and progression of lung squamous cell carcinoma by disrupting the tumor-suppressor gene FGGY
AU - Zhang, Rui
AU - Zhang, Fan
AU - Sun, Zeguo
AU - Liu, Pengpeng
AU - Zhang, Xiao
AU - Ye, Yingnan
AU - Cai, Beiqi
AU - Walsh, Martin J.
AU - Ren, Xiubao
AU - Hao, Xishan
AU - Zhang, Weijia
AU - Yu, Jinpu
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Somatic long interspersed element-1 (LINE-1) retrotransposition is a genomic process that relates to gene disruption and tumor occurrence. However, the expression and function of LINE-1 retrotransposition in lung squamous cell carcinoma (LUSC) remain unclear. We analyzed the transcriptomes of LUSC samples in The Cancer Genome Atlas and observed LINE-1 retrotransposition in 90% of tumor samples. Thirteen LINE-1 retrotranspositions of high occurrence were identified and further validated from an independent Chinese LUSC cohort. Among them, LINE-1-FGGY (L1-FGGY) was identified as the most frequent LINE-1 retrotransposition in the Chinese cohort and significantly correlated with poor clinical outcome. L1-FGGY occurred with smoke-induced hypomethylation of the LINE-1 promoter and contributed to the development of local immune evasion and dysfunctional metabolism. Overexpression of L1-FGGY or knockdown of FGGY promoted cell proliferation and invasion in vitro, facilitated tumorigenesis in vivo, and dysregulated cell energy metabolism and cytokine/ chemotaxin transcription. Importantly, specific reverse transcription inhibitors, nevirapine and efavirenz, dramatically countered L1-FGGY abundance, inhibited tumor growth, recovered metabolism dysfunction, and improved the local immune evasion. In conclusion, hypomethylation-induced L1-FGGY 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.
AB - Somatic long interspersed element-1 (LINE-1) retrotransposition is a genomic process that relates to gene disruption and tumor occurrence. However, the expression and function of LINE-1 retrotransposition in lung squamous cell carcinoma (LUSC) remain unclear. We analyzed the transcriptomes of LUSC samples in The Cancer Genome Atlas and observed LINE-1 retrotransposition in 90% of tumor samples. Thirteen LINE-1 retrotranspositions of high occurrence were identified and further validated from an independent Chinese LUSC cohort. Among them, LINE-1-FGGY (L1-FGGY) was identified as the most frequent LINE-1 retrotransposition in the Chinese cohort and significantly correlated with poor clinical outcome. L1-FGGY occurred with smoke-induced hypomethylation of the LINE-1 promoter and contributed to the development of local immune evasion and dysfunctional metabolism. Overexpression of L1-FGGY or knockdown of FGGY promoted cell proliferation and invasion in vitro, facilitated tumorigenesis in vivo, and dysregulated cell energy metabolism and cytokine/ chemotaxin transcription. Importantly, specific reverse transcription inhibitors, nevirapine and efavirenz, dramatically countered L1-FGGY abundance, inhibited tumor growth, recovered metabolism dysfunction, and improved the local immune evasion. In conclusion, hypomethylation-induced L1-FGGY 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.
UR - http://www.scopus.com/inward/record.url?scp=85071787202&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-0076
DO - 10.1158/0008-5472.CAN-19-0076
M3 - Article
C2 - 31289132
AN - SCOPUS:85071787202
SN - 0008-5472
VL - 79
SP - 4453
EP - 4465
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -