Targeting CHD1L Suppresses Prostate Cancer Progression via the FOXO3-PUMA Axis

Prostate cancer (PCa) is one of the most prevalent malignancies in men and remains a major cause of cancer-related mortality worldwide. While taxane-based chemotherapies, such as docetaxel, are standard treatment options for metastatic castration-resistant prostate cancer (mCRPC), their long-term efficacy is limited. This highlights an urgent need for new therapeutic targets and more effective treatment strategies to improve survival in advanced PCa. Here, we show that CHD1L is overexpressed in prostate cancer tissues and correlates with poor prognosis. Knockdown of CHD1L substantially inhibits PCa cell proliferation and induces apoptosis. Moreover, inhibition of CHD1L by the small molecule OTI-611 significantly suppresses PCa cell proliferation, migration, and invasion, and induces apoptosis both in vitro and in vivo. Mechanistically, inhibition of CHD1L induces the expression of FOXO3 (a classic transcription factor) and its downstream target PUMA (a key apoptosis inducer). Restricting the expression of FOXO3 substantially reverses the anti-tumor effects induced by OTI-611. Furthermore, OTI-611 synergizes with docetaxel to enhance apoptotic cell death, providing a promising strategy to overcome docetaxel resistance. These findings highlight the therapeutic potential of targeting CHD1L in combination with existing treatments, offering a novel approach for the treatment of advanced prostate cancer. Overall design: DU145 cells were treated with vehicle (DMSO) or OTI-611 (5 µM) for 24 h. The cells were collected for RNA-seq analysis