Li Chunfei, Guan Wenzheng, Geng Donghua, Feng Yong
Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, 110004, Shenyang, China.
Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
Cell Biol Toxicol. 2025 Jan 6;41(1):22. doi: 10.1007/s10565-024-09977-z.
RING finger protein 112 (RNF112) exerts a key role in human tumors. However, its biological function in colorectal cancer (CRC) has not been discussed. We aimed to explore the function and molecular mechanism of RNF112 in CRC.
In this study, RNF112 expression was notably decreased in CRC tissues and cells. Clinical analysis revealed a significant association between low RNF112 expression and tumor size, N classification and TNM stage. In vitro experiments demonstrated that overexpression of RNF112 repressed cell viability, promoted cell cycle arrest and apoptosis, while knocking down RNF112 had the opposite function. The tumor formation results in nude mice supported that RNF112 overexpression exerted anti-tumor effects by inhibiting cell growth and promoting cell apoptosis. Mechanistically, Krüppel-like factor 4 (KLF4) acted as an upstream regulator of RNF112 by mediating its transcription. Furthermore, we explored the downstream mechanism of RNF112 and discovered that it promoted ubiquitination and degradation of oncoprotein N-alpha-acetyltransferase 40 (NAA40) through ubiquitin ligase activity. In addition, overexpression of NAA40 eliminated the effect of RNF112 overexpression on CRC tumorigenesis.
In summary, our findings confirm that RNF112, whose transcription is regulated by KLF4, inhibits CRC growth through promoting ubiquitin-dependent degradation of NAA40. We have unraveled the mechanism of KLF4-RNF112-NAA40 axis in CRC, which shed light on the therapeutic strategies for this disease.
环指蛋白112（RNF112）在人类肿瘤中发挥关键作用。然而，其在结直肠癌（CRC）中的生物学功能尚未见讨论。我们旨在探讨RNF112在CRC中的功能及分子机制。
在本研究中，CRC组织和细胞中RNF112表达显著降低。临床分析显示，RNF112低表达与肿瘤大小、N分期及TNM分期之间存在显著关联。体外实验表明，RNF112过表达抑制细胞活力，促进细胞周期阻滞和凋亡，而敲低RNF112则具有相反作用。裸鼠成瘤结果支持RNF112过表达通过抑制细胞生长和促进细胞凋亡发挥抗肿瘤作用。机制上，Krüppel样因子4（KLF4）通过介导RNF112的转录而作为其上游调节因子。此外，我们探究了RNF112的下游机制，发现它通过泛素连接酶活性促进癌蛋白N-α-乙酰转移酶40（NAA40）的泛素化和降解。另外，NAA40过表达消除了RNF112过表达对CRC肿瘤发生的影响。
总之，我们的研究结果证实，转录受KLF4调控的RNF112通过促进NAA40的泛素依赖性降解来抑制CRC生长。我们揭示了CRC中KLF4-RNF112-NAA40轴的机制，为该疾病的治疗策略提供了线索。
