Fatty Acid 2-hydroxylation Attenuates Tumor Growth And Metastasis In Colorectal Cancer Via Targeting YAP

Background and Objective: Colorectal cancer is the third most malignancy and one of the leading causes of cancer-related death worldwide.The enzyme fatty acid2-hydroxylase(FA2H)with high expression in colon introduces(R)-2-OHFAs which is important for cell growth and apoptosis.Here,we aimed to investigate the potential role of FA2 H in the development and progression of colorectal cancer.Methods: FA2 H levels were analyzed in human colorectal cancer and adjacent normal tissues by Western blots and immunohistochemistry.Potential roles of FA2 H and its enzymatic product(R)-2-OHPA in regulating colorectal cancer cell growth and metastasis were examined by genetic manipulation in vitro.The molecular signaling were determined to understand the mechanisms of observed FA2 H effects.Results: FA2 H level was lower in colorectal cancer tissues as compared to normal tissues and its expression was significantly associated with tumor size,lymph node metastasis and survival.FA2 H overexpression or treatment with its product(R)-2-OHPA suppressed colorectal cancer cell growth and metastasis while FA2 H depletion had the opposite effect.FA2 H regulated epithelial-mesenchymal transition(EMT)through a YAP-dependent pathway in colorectal cancer cells.The observed effects of FA2 H and(R)-2-OHPA on the inactivation of YAP was dependent on the activation of AMPK.Conclusions: Our results demonstrate that FA2 H or(R)-2-OHPA plays a vital role in regulating Hippo-YAP signaling and colorectal cancer cell growth and metastasis,indicating that(R)-2-OHPA could serve as a promising drug to kill cancer.