Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai Yangpu, China.
Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, Yangpu, China.
Autophagy. 2023 Mar;19(3):805-821. doi: 10.1080/15548627.2022.2103992. Epub 2022 Aug 3.
Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the lack of effective targeted therapies. Transmembrane (TMEM) proteins represent attractive drug targets for cancer therapy, but biological functions of most members of the TMEM family remain unknown. Here, we report for the first time that TMEM63A (transmembrane protein 63A), a poorly characterized TMEM protein with unknown functions in human cancer, functions as a novel oncogene to promote TNBC cell proliferation, migration, and invasion and xenograft tumor growth and lung metastasis . Mechanistic investigations revealed that TMEM63A localizes in endoplasmic reticulum (ER) and lysosome membranes, and interacts with VCP (valosin-containing protein) and its cofactor DERL1 (derlin 1). Furthermore, TMEM63A undergoes autophagy receptor TOLLIP-mediated autophagic degradation and is stabilized by VCP through blocking its lysosomal degradation. Strikingly, TMEM63A in turn stabilizes oncoprotein DERL1 through preventing TOLLIP-mediated autophagic degradation. Notably, pharmacological inhibition of VCP by CB-5083 or knockdown of DERL1 partially abolishes the oncogenic effects of TMEM63A on TNBC progression both and . Collectively, these findings uncover a previously unknown functional and mechanistic role for TMEM63A in TNBC progression and provide a new clue for targeting TMEM63A-driven TNBC tumors by using a VCP inhibitor. ATG16L1, autophagy related 16 like 1; ATG5, autophagy related 5; ATP5F1B/ATP5B, ATP synthase F1 subunit beta; Baf-A1, bafilomycin A; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CANX, calnexin; DERL1, derlin 1; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; HSPA8, heat shock protein family A (Hsp70) member 8; IP, immunoprecipitation; LAMP2A, lysosomal associated membrane protein 2; NBR1, NBR1 autophagy cargo receptor; OPTN, optineurin; RT-qPCR, reverse transcription-quantitative PCR; SQSTM1/p62, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TMEM63A, transmembrane protein 63A; TNBC, triple-negative breast cancer; TOLLIP, toll interacting protein; VCP, valosin containing protein.
三阴性乳腺癌（TNBC）是治疗最具挑战性的乳腺癌亚型，因为缺乏有效的靶向治疗方法。跨膜（TMEM）蛋白是癌症治疗的有吸引力的药物靶点，但大多数 TMEM 家族成员的生物学功能仍然未知。在这里，我们首次报道了 TMEM63A（跨膜蛋白 63A），这是一种功能未知的人类癌症中特征不明显的 TMEM 蛋白，作为一种新型癌基因促进 TNBC 细胞增殖、迁移和侵袭，以及异种移植肿瘤生长和肺转移。机制研究表明，TMEM63A 定位于内质网（ER）和溶酶体膜，并与 VCP（含缬氨酸蛋白）及其辅助因子 DERL1（derlin 1）相互作用。此外，TMEM63A 通过 TOLLIP 介导的自噬降解的自噬受体进行自噬降解，并通过阻止其溶酶体降解被 VCP 稳定。引人注目的是，TMEM63A 反过来通过防止 TOLLIP 介导的自噬降解稳定癌蛋白 DERL1。值得注意的是，通过 CB-5083 抑制 VCP 或敲低 DERL1 部分消除了 TMEM63A 对 TNBC 进展的致癌作用。总的来说，这些发现揭示了 TMEM63A 在 TNBC 进展中的一个以前未知的功能和机制作用，并为通过使用 VCP 抑制剂靶向 TMEM63A 驱动的 TNBC 肿瘤提供了一个新的线索。ATG16L1、自噬相关 16 样 1；ATG5、自噬相关 5；ATP5F1B/ATP5B、ATP 合酶 F1 亚基β；Baf-A1、巴弗霉素 A；CALCOCO2/NDP52、钙结合和卷曲螺旋结构域 2；CANX、钙网蛋白；DERL1、derlin 1；EGFR、表皮生长因子受体；ER、内质网；ERAD、内质网相关降解；HSPA8、热休克蛋白家族 A（Hsp70）成员 8；IP、免疫沉淀；LAMP2A、溶酶体相关膜蛋白 2；NBR1、NBR1 自噬货物受体；OPTN、optineurin；RT-qPCR、逆转录定量 PCR；SQSTM1/p62、自噬体 1；TAX1BP1、Tax1 结合蛋白 1；TMEM63A、跨膜蛋白 63A；TNBC、三阴性乳腺癌；TOLLIP、toll 相互作用蛋白；VCP、含缬氨酸蛋白。
