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Accumulating evidence has shown that H6 Family Homeobox 3 (HMX3) plays a crucial role in nervous system regulation. However, the regulatory mechanism of HMX3 in colorectal cancer (CRC) has seldom been studied. Herein, HMX3 was significantly downregulated in CRC, as demonstrated by qRT-PCR and WB analysis on clinical samples and a panel of cell lines. Besides, it was found that the expression of HMX3 was negatively correlated with survival of CRC patients. The functional analyses (EdU staining, CCK-8, colony formation, Transwell, and wound scratch assays) showed that CRC cell proliferation, migration, and invasion were significantly suppressed by HMX3 overexpression, while enhanced by HMX3 knockdown. Moreover,  in vivo  experiment revealed HMX3 overexpression could also suppress tumor growth. Combining bioinformatics and WB analysis, we preliminarily uncovered that HMX3 was involved in apoptosis and KRAS signaling pathways. Mechanistically, Ubiquitin-specific protease 38 (USP38) was identified as a novel post-translational regulator of HMX3, which could directly interact with HMX3 to stabilize its protein expression via deubiquitination. Furthermore, the role of USP38 silencing in promoting cell proliferation, migration, and invasion of CRC cells was blocked by HMX3 overexpression. In conclusion, our findings suggested that USP38/HMX3 axis is a novel promising therapeutic candidate for CRC.

USP38 inhibits colorectal cancer cell proliferation and migration via downregulating HMX3 ubiquitylation