Zheng Wenfang, Luo Qifeng, Wang Xuehui, Zhou Xiqian, Ye Danrong, Hua Kaiyao, Fang Lin
Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
Int J Biol Sci. 2025 Jun 20;21(9):4172-4186. doi: 10.7150/ijbs.99438. eCollection 2025.
Triple-negative breast cancer (TNBC) was a subtype of breast cancer with high rate of metastasis and poor prognosis. Thus, it is urgent to explore the underlying mechanism of TNBC metastasis and seek for potential therapeutic targets to improve the prognosis of TNBC patients. Here we reported that nuclear autoantigenic sperm protein (NASP) was highly expressed in TNBC and related to poor prognosis of TNBC patients. NASP acted as an oncogene that promoted the progression and metastasis of TNBC. Mechanistically, high expression of NASP in TNBC was induced by SRSF1-mediated stabilization of NASP mRNA. NASP interacted with USP15 and facilitated its activity, which resulted in the deubiquitylation and stabilization of YAP by erasing K48-linked polyubiquitination. Moreover, in vivo studies validated the role of NASP in stimulating TNBC growth and metastasis. Altogether, NASP promoted TNBC progression and metastasis by stabilizing YAP in a USP15-dependent way. It might provide new insights and potential therapeutic targets for preventing TNBC metastasis and improving the prognosis of TNBC patients.
三阴性乳腺癌（TNBC）是一种转移率高、预后差的乳腺癌亚型。因此，迫切需要探索TNBC转移的潜在机制，并寻找潜在的治疗靶点以改善TNBC患者的预后。在此我们报道，核自身抗原性精子蛋白（NASP）在TNBC中高表达，且与TNBC患者的不良预后相关。NASP作为一种癌基因，促进TNBC的进展和转移。机制上，TNBC中NASP的高表达是由SRSF1介导的NASP mRNA稳定化所诱导。NASP与USP15相互作用并促进其活性，通过消除K48连接的多聚泛素化导致YAP的去泛素化和稳定化。此外，体内研究验证了NASP在刺激TNBC生长和转移中的作用。总之，NASP通过以USP15依赖的方式稳定YAP来促进TNBC的进展和转移。它可能为预防TNBC转移和改善TNBC患者的预后提供新的见解和潜在的治疗靶点。
