3-hydroxyanthranilic acid suppresses colorectal cancer growth and enhances 5-fluorouracil sensitivity via the YY1-p53 and YY1-DKK4 axes

Abstract

The tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) has been reported to exert tumor-growth-inhibitory activity; however, its functional role and underlying mechanisms in colorectal cancer (CRC) remain largely unexplored. We measured 3-HAA levels in CRC tissues and evaluated its effects on CRC cell proliferation through exogenous administration. Mechanistic investigations were performed to identify its direct protein targets and downstream signaling pathways. The therapeutic potential of 3-HAA, alone and in combination with 5-fluorouracil (5-FU), was assessed both in vitro and in vivo using cell line-derived xenograft mouse model and AOM/DSS-induced colorectal tumor mouse model. 3-HAA exhibited depleted levels in CRC tissues, and its exogenous administration effectively suppressed the proliferation of multiple CRC cell lines. Through its binding to the Yin Yang 1 (YY1) transcription factor, it disrupted the YY1-p53 interaction, preserved p53 stability, and induced cell cycle arrest. Notably, in vitro , 3-HAA reduced chemoresistance to the common CRC-chemotherapy drug 5-fluorouracil (5-FU) via the YY1-DKK4 axis. Consistently, in vivo , combined 3-HAA-5-FU treatment effectively inhibited CRC progression. Our findings demonstrate that 3-HAA functions as a tumor suppressor in CRC by targeting the YY1–p53 axis and enhancing chemosensitivity to 5-FU. These results highlight the potential of 3-HAA as a promising therapeutic agent for CRC treatment.