Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, 210023, China.
Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing, 210023, China.
Mol Med. 2023 Jun 6;29(1):72. doi: 10.1186/s10020-023-00663-0.
Mitochondrial metabolism has been proposed as an attractive target for breast cancer therapy. The discovery of new mechanisms underlying mitochondrial dysfunction will facilitate the development of new metabolic inhibitors to improve the clinical treatment of breast cancer patients. DYNLT1 (Dynein Light Chain Tctex-Type 1) is a key component of the motor complex that transports cellular cargo along microtubules in the cell, but whether and how DYNLT1 affects mitochondrial metabolism and breast cancer has not been reported.
The expression levels of DYNLT1 were analyzed in clinical samples and a panel of cell lines. The role of DYNLT1 in breast cancer development was investigated using in vivo mouse models and in vitro cell assays, including CCK-8, plate cloning and transwell assay. The role of DYNLT1 in regulating mitochondrial metabolism in breast cancer development is examined by measuring mitochondrial membrane potential and ATP levels. To investigate the underlying molecular mechanism, many methods, including but not limited to Co-IP and ubiquitination assay were used.
First, we found that DYNLT1 was upregulated in breast tumors, especially in ER + and TNBC subtypes. DYNLT1 promotes the proliferation, migration, invasion and mitochondrial metabolism in breast cancer cells in vitro and breast tumor development in vivo. DYNLT1 colocalizes with voltage-dependent anion channel 1 (VDAC1) on mitochondria to regulate key metabolic and energy functions. Mechanistically, DYNLT1 stabilizes the voltage-dependent anion channel 1 (VDAC1) by hindering E3 ligase Parkin-mediated VDAC1 ubiquitination and degradation.
Our data demonstrate that DYNLT1 promotes mitochondrial metabolism to fuel breast cancer development by inhibiting Parkin-mediated ubiquitination degradation of VDAC1. This study suggests that mitochondrial metabolism can be exploited by targeting the DYNLT1-Parkin-VDAC1 axis to improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC).
线粒体代谢已被提议作为乳腺癌治疗的一个有吸引力的靶点。新的线粒体功能障碍机制的发现将有助于开发新的代谢抑制剂，以改善乳腺癌患者的临床治疗效果。DYNLT1（动力蛋白轻链 Tctex 型 1）是沿细胞中的微管运输细胞货物的运动复合物的关键组成部分，但 DYNLT1 是否以及如何影响线粒体代谢和乳腺癌尚未报道。
分析了临床样本和一系列细胞系中 DYNLT1 的表达水平。通过体内小鼠模型和体外细胞实验（包括 CCK-8、平板克隆和 Transwell 测定）研究了 DYNLT1 在乳腺癌发展中的作用。通过测量线粒体膜电位和 ATP 水平来研究 DYNLT1 在调节乳腺癌发展中线粒体代谢中的作用。为了研究潜在的分子机制，使用了许多方法，包括但不限于 Co-IP 和泛素化测定。
首先，我们发现 DYNLT1 在乳腺癌肿瘤中上调，特别是在 ER+和三阴性乳腺癌（TNBC）亚型中。DYNLT1 在体外促进乳腺癌细胞的增殖、迁移、侵袭和线粒体代谢，以及体内促进乳腺癌肿瘤的发展。DYNLT1 与电压依赖性阴离子通道 1（VDAC1）在线粒体上共定位，以调节关键的代谢和能量功能。在机制上，DYNLT1 通过阻止 E3 连接酶 Parkin 介导的 VDAC1 泛素化和降解来稳定电压依赖性阴离子通道 1（VDAC1）。
我们的数据表明，DYNLT1 通过抑制 Parkin 介导的 VDAC1 泛素化降解来促进线粒体代谢，从而促进乳腺癌的发展。这项研究表明，通过靶向 DYNLT1-Parkin-VDAC1 轴，可以利用线粒体代谢来改善代谢抑制剂抑制治疗选择有限的癌症（如三阴性乳腺癌）的能力。
