The protein posttranslational modifications, including ubiquitination and methylation, exhibit the essential function in breast cancer. Herein, we aimed to explore the molecular mechanism of neural precursor cell-expressed developmentally downregulated gene 4-like (NEDD4L) associated with Rho GTPase Rif (RHOF) and AlkB homolog 5 (ALKBH5). A series of experiments including expression detection, cell functions, xenograft tumor assay, and interaction analysis were designed.

RHOF was up-regulated in breast cancer samples and cells. Silencing RHOF suppressed breast cancer cell growth, migration, invasion and lipid metabolism. Breast cancer tumorigenesis and lipid metabolism were repressed by RHOF knockdown in vivo. NEDD4L impaired RHOF stability by promoting its ubiquitination. NEDD4L overexpression restrained breast cancer cell progression and lipid metabolism via degrading RHOF. ALKBH5 inhibited NEDD4L expression through m6A modification.