FOXO1-regulated lncRNA CYP1B1-AS1 suppresses breast cancer cell proliferation by inhibiting neddylation

Purpose: Overactivated neddylation is considered to be a common event in Cancer. Long non-coding RNAs (lncRNAs) can regulate Cancer development by mediating post-translational modifications. However, the role of lncRNA in neddylation modification remains unclear.

Methods: LncRNA Cytochrome P450 family 1 subfamily B member 1 antisense RNA 1 (CYP1B1-AS1) expression in breast Cancer tissues was evaluated by RT-PCR and TCGA BRCA data. Gain and loss of function experiments were performed to explore the role of CYP1B1-AS1 in breast Cancer cell proliferation and Apoptosis in vitro and in vivo. Luciferase assay, CHIP-qPCR assay, transcriptome sequencing, RNA-pulldown assay, mass spectrometry, RIP-PCR and Western blot were used to investigate the regulatory factors of CYP1B1-AS1 expression and the molecular mechanism of CYP1B1-AS1 involved in neddylation modification.

Results: We found that CYP1B1-AS1 was down-regulated in breast Cancer tissues and correlated with prognosis. In vivo and in vitro functional experiments confirmed that CYP1B1-AS1 inhibited cell proliferation and induced Apoptosis. Mechanistically, CYP1B1-AS1 was regulated by the transcription factor, forkhead box O1 (FOXO1), and could be upregulated by inhibiting the PI3K/FOXO1 pathway. Moreover, CYP1B1-AS1 bound directly to NEDD8 activating Enzyme E1 subunit 1 (NAE1) to regulate protein neddylation.

Conclusion: This study reports for the first time that CYP1B1-AS1 inhibits protein neddylation to affect breast Cancer cell proliferation, which provides a new strategy for the treatment of breast Cancer by lncRNA targeting neddylation modification.

Breast cancer; FOXO1; Long noncoding RNA; NAE1; NEDD8; Neddylation.