Yan Zhengwei, Huang Aidi, Ma Dongwen, Hong Chenao, Zhang Shengmiao, He Luling, Rao Hai, Luo Shiwen
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China.
Cell Death Dis. 2025 Mar 25;16(1):201. doi: 10.1038/s41419-025-07534-y.
Autophagy is a highly conserved cellular process essential for maintaining cellular homeostasis and influencing cancer development. Lysosomal acidification and autophagosome-lysosome fusion are two important steps of autophagy degradation that are tightly regulated. Although many key proteins that regulate these two events have been identified, the effector proteins that co-regulate both steps remain to be explored. ATP6AP1, an accessory subunit of V-ATPase, plays a critical role in the assembly and regulation of V-ATPase. However, the function of ATP6AP1 in autophagy remains unknown, and the role of ATP6AP1 in cancer is still poorly understood. In this study, we found that ATP6AP1 is overexpressed in luminal breast cancer tissues and promotes the proliferation and tamoxifen resistance of luminal breast cancer cells both in vitro and in vivo. We also observed that high ATP6AP1 expression correlates with poor overall patient survival. Our research further revealed that ATP6AP1 enhances tamoxifen resistance by activating autophagy. Mechanistically, ATP6AP1 promotes autophagy by regulating both lysosomal acidification and autophagosome-lysosome fusion. Remarkably, ATP6AP1 induces lysosomal acidification through the regulation of V-ATPase assembly and facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS complex. Together, our studies identify ATP6AP1 as a crucial regulator of autophagy, potentially serving as a valuable prognostic marker or therapeutic target in human luminal breast cancer.
自噬是一种高度保守的细胞过程，对于维持细胞内稳态和影响癌症发展至关重要。溶酶体酸化和自噬体-溶酶体融合是自噬降解的两个重要步骤，受到严格调控。尽管已经鉴定出许多调节这两个事件的关键蛋白，但共同调节这两个步骤的效应蛋白仍有待探索。ATP6AP1是V-ATP酶的一个辅助亚基，在V-ATP酶的组装和调节中起关键作用。然而，ATP6AP1在自噬中的功能仍然未知，其在癌症中的作用也仍未得到充分了解。在本研究中，我们发现ATP6AP1在管腔型乳腺癌组织中过表达，并在体外和体内促进管腔型乳腺癌细胞的增殖和他莫昔芬耐药性。我们还观察到ATP6AP1高表达与患者总体生存率低相关。我们的研究进一步揭示，ATP6AP1通过激活自噬增强他莫昔芬耐药性。机制上，ATP6AP1通过调节溶酶体酸化和自噬体-溶酶体融合来促进自噬。值得注意的是，ATP6AP1通过调节V-ATP酶组装诱导溶酶体酸化，并通过增强Rab7与HOPS复合物之间的相互作用促进自噬体-溶酶体融合。总之，我们的研究确定ATP6AP1是自噬的关键调节因子，可能成为人类管腔型乳腺癌中有价值的预后标志物或治疗靶点。
