BHLHA15 promotes cervical cancer cholesterol synthesis and tumor progression

Research suggested that increased cholesterol synthesis is an effect factor in the malignant progression and unfavorable outcome of cervical cancer (CC). Unfortunately, the molecular mechanisms underlying the increased cholesterol synthesis remain elusive. Here, our comprehensive bioinformatics analysis, along with in vitro and in vivo experimental validations, suggests that basic helix-loop-helix family member a15 (BHLHA15) is a pivotal transcription factor (TF) regulating cholesterol synthesis and malignant progression in CC. Our results indicates that BHLHA15, along with its target genes CYP51A1 and FASN, are significantly upregulated in CC tissues, particularly in III-IV stages and dead patients, indicating a strong association with poor prognosis. Additionally, ectopic expression of BHLHA15 increases the levels of free and total cholesterol, thereby enhancing cancer progression in CC cells. Mechanistically, BHLHA15 directly binds and activates the expression of CYP51A1 and FASN, thereby promoting cholesterol synthesis and progression of CC. Notably, stable knockdown of BHLHA15 effectively suppresses the CC progression by suppressing the expression of CYP51A1 and FASN. Furthermore, risk models based on the expression levels of BHLHA15, CYP51A1, and FASN exhibits excellently diagnostic and prognostic efficacy in CC. Collectively, we identified BHLHA15 as a critical TF that regulates cholesterol synthesis in CC, and provides a potentially effective strategy for targeted therapy in CC.