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LncPSCA in the 8q24.3 risk locus drives gastric cancer through destabilizing DDX5
Author(s) -
Zheng Yan,
Lei Tianshui,
Jin Guangfu,
Guo Haiyang,
Zhang Nasha,
Chai Jie,
Xie Mengyu,
Xu Yeyang,
Wang Tianpei,
Liu Jiandong,
Shen Yue,
Song Yemei,
Wang Bowen,
Yu Jinming,
Yang Ming
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202152707
Subject(s) - locus (genetics) , biology , genetics , medicine , gene
Genome‐wide association studies (GWAS) have identified multiple gastric cancer risk loci and several protein‐coding susceptibility genes. However, the role of long‐noncoding RNAs (lncRNAs) transcribed from these risk loci in gastric cancer development and progression remains to be explored. Here, we functionally characterize a lncRNA, lncPSCA, as a novel tumor suppressor whose expression is fine‐regulated by a gastric cancer risk‐associated genetic variant. The rs2978980 T > G change in an intronic enhancer of lncPSCA interrupts binding of transcription factor RORA, which down‐regulates lncPSCA expression in an allele‐specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation through ubiquitination. Increased expression of lncPSCA results in low levels of DDX5, less RNA polymerase II (Pol II) binding with DDX5 in the nucleus, thus activating transcription of multiple p53 signaling genes by Pol II. These findings highlight the importance of functionally annotating lncRNAs in GWAS risk loci and the great potential of modulating lncRNAs as innovative cancer therapy.