The
E3 ubiquitin ligase RING finger
protein 6 (RNF6) is elevated in several
cancers, including prostate and
colorectal cancers. Here, we extended the finding of elevated RNF6 expression levels and its association with poor prognosis in patients with
lung adenocarcinoma (LUAD). Genome-wide
RNA sequencing in H3255 cells with RNF6 knockdown, followed by analysis of differentially expressed genes using Clusters of Orthologous Groups and gene set enrichment analysis revealed aberrations in genes related to DNA repair, especially double-strand break (
DSB) repair. RNF6 knockdown increased γH2AX foci, a
biomarker for DSBs in H3255 and A549 LUAD cells, and enhanced DNA damage induced by
chemotherapy in
cisplatin-resistant A549/CDDP cells. In a series of experiments in cultured cells, as well as in nude mice carrying xenografts, RNF6 knockdown restored the sensitivity of A549/CDDP cells to
cisplatin treatment. Mechanistically,
RNA sequencing in RNF6-knockdown cells revealed the significant downregulation of
proliferating cell nuclear antigen (
PCNA), an oncogene that promotes DNA repair. Re-
chromatin immunoprecipitation assay results suggested the formation of a RNF6-TCF4 complex that binds to the
PCNA promoter to activate its transcription. Downregulation of RNF6 reduced TCF4 recruitment to
PCNA promoters in H3255 and A549 cells, indicating that RNF6 regulates
PCNA transcription to a certain extent by regulating TCF4 binding to
PCNA promoters. The collective results implicate RNF6 overexpression as a molecular target in the management of
cisplatin-resistant LUAD.