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Non-coding SNP at rs1663689 represses ADGRG6 via interchromosomal interaction and reduces lung cancer progression

ABSTRACT: A previous genome-wide association study (GWAS) revealed an association of the non-coding SNP rs1663689 with susceptibility to lung cancer in the Chinese population. However, the underlying mechanism is unknown. In this study, using allele-specific 4C-seq in heterozygous lung cancer cells combined with epigenetic information from CRISPR/Cas9-edited cell lines, we show that the rs1663689 C/C variant represses expression of ADGRG6, a gene located on a separate chromosome, through an interchromosomal interaction of the rs1663689 bearing region with the ADGRG6 promoter. This reduces downstream cAMP-PKA signaling and subsequently tumor growth both in vitro and in xenograft models. Using patient-derived organoids, we show that rs1663689 T/T - but not C/C - bearing lung tumors are sensitive to the PKA inhibitor H89, potentially informing therapeutic strategies. Our study identifies a genetic variant-mediated interchromosomal interaction underlying ADGRG6 regulation and suggests that targeting the cAMP-PKA signaling pathway may be beneficial in lung cancer patients bearing the homozygous risk genotype at rs1663689.

SUBMITTER: Dr. Xinyue Lei

PROVIDER: S-SCDT-10_15252-EMBR_202256212 | biostudies-other |

REPOSITORIES: biostudies-other

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