Targeting CHD1L suppresses prostate cancer progression via the FOXO3-PUMA axis

Background Prostate cancer (PCa) is one of the most common malignancies in men worldwide, and advanced or metastatic disease remains a major therapeutic challenge. Chromodomain helicase DNA binding protein 1-like (CHD1L) has been implicated as an oncogenic driver in multiple cancer types, yet its role in prostate cancer pathogenesis is not fully defined. The purpose of this study is to investigate the biological significance of CHD1L in prostate cancer and to evaluate the therapeutic potential of its selective inhibitor OTI-611. Methods Bioinformatics analyses were conducted to assess the expression, prognostic significance of CHD1L in PCa patients. In vitro , cell viability, cycle progression, apoptosis, and migration/invasion were evaluated using CCK-8, colony formation, flow cytometry, transwell assays. In vivo treatment potential of OTI-611 was assessed through a nude mouse xenograft model. Protein and mRNA levels were determined by western blot and qPCR, respectively. Synergism of OTI-611 and docetaxel was determined using SynergyFinder 3.0. Results We demonstrated that CHD1L was significantly upregulated in PCa patients and correlates with poor prognosis. Genetic 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 significantly 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. Conclusions Our study demonstrates that CHD1L is markedly upregulated in prostate cancer and contributes to tumor progression. Pharmacological inhibition of CHD1L with the selective inhibitor OTI-611 significantly suppresses proliferation, migration, and invasion, while inducing apoptosis in vitro and in vivo . Mechanistically, these effects are mediated through activation of the FOXO3–PUMA axis, as FOXO3 suppression abrogates OTI-611–induced apoptosis. Moreover, OTI-611 exhibits strong synergy with docetaxel, enhancing apoptotic cell death and providing a potential strategy to improve therapeutic efficacy in prostate cancer.