Reciprocal Regulation of ASPM and FoxM1

Fork-head box protein M1 (FoxM1) is a transcription factor which plays critical roles in development and progression of multiple cancers, including human hepatocellular carcinoma (HCC). However, the regulatory mechanism of FoxM1 itself remains largely unclear. Here, we discovered a novel role of abnormal spindle-like microcephaly associated (ASPM) in HCC, which binds to FoxM1 protein and enhances its stability by preventing proteasome-mediated degradation. ChIP-sequencing data showed that ASPM and FoxM1 co-occupies on the promoter region of multiple genes to promote their transcriptions, leading to the enhancement of a FoxM1-driven oncogenic progression. Intriguingly, FoxM1 binds to the promoter region of ASPM and transcriptionally activates the ASPM expression. Furthermore, data from clinical samples showed that a higher co-expression of ASPM and FoxM1 significantly correlates with poor prognosis in HCC, indicating that a positive feedforward loop between ASPM and FoxM1 coordinately promotes the aggressive progression in HCC. Collectively, our study reveals that reciprocal regulation of ASPM and FoxM1 amplifies the oncogenic progression and emphasizes an ASPM-FoxM1 feedforward loop could be a potential biomarker and therapeutic target in HCC.