Li Jutao, Gao Zhenming
Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Dalian Medical University, Dalian, China.
Organ Transplantation Center, The Second Hospital of Dalian Medical University, Dalian, China.
Cell Biol Int. 2025 Feb;49(2):161-176. doi: 10.1002/cbin.12255. Epub 2024 Oct 20.
Breast cancer has become the leading cause of death in women. Membrane associated ring-CH-type finger 1 (MARCHF1) is associated with the development of various types of cancer, but the exact role of MARCHF1 in breast cancer remains unclear. In our study, the higher MARCHF1 expression was observed in tumor samples of patients with breast cancer and then the role of MARCHF1 in breast cancer was further evaluated. Overexpression of MARCHF1 contributed to proliferation of cancer cells and inhibition of oxidative stress. Knockdown of MARCHF1 reduced breast cancer cell proliferation, increased mitochondrial dysfunction induced by oxidative stress, eventually aggravating cell death. In vivo, MARCHF1 promoted the tumor growth and oppositely, MARCHF1 silencing suppressed the tumor development. Moreover, MARCHF1 interacted with repressor Element-1 silencing transcription factor (REST) and facilitated its ubiquitylation and degradation. Subsequently, REST negatively regulated the transcription of mitochondrial transcription factor A (TFAM). The subcutaneous tumor formation assay in nude mice also supported these conclusions. In details, knockdown of MARCHF1 upregulated the protein expression of REST and downregulated the mRNA level of TFAM. On the contrary, MARCHF1 overexpression exhibited opposite effects. Thus, MARCHF1 is conducive to the progression of breast cancer via promoting the ubiquitylation and degradation of RSET and then the transcription of TFAM. Downregulating MARCHF1 could provide a novel direction for treating breast cancer.
乳腺癌已成为女性死亡的主要原因。膜相关环-CH型指蛋白1（MARCHF1）与多种癌症的发生发展相关，但MARCHF1在乳腺癌中的确切作用仍不清楚。在我们的研究中，观察到乳腺癌患者肿瘤样本中MARCHF1表达较高，进而对MARCHF1在乳腺癌中的作用进行了进一步评估。MARCHF1的过表达促进癌细胞增殖并抑制氧化应激。敲低MARCHF1可降低乳腺癌细胞增殖，增加氧化应激诱导的线粒体功能障碍，最终加重细胞死亡。在体内，MARCHF1促进肿瘤生长，相反，沉默MARCHF1可抑制肿瘤发展。此外，MARCHF1与阻遏元件-1沉默转录因子（REST）相互作用，并促进其泛素化和降解。随后，REST负向调节线粒体转录因子A（TFAM）的转录。裸鼠皮下肿瘤形成实验也支持了这些结论。具体而言，敲低MARCHF1可上调REST蛋白表达并下调TFAM的mRNA水平。相反，MARCHF1过表达则表现出相反的效果。因此，MARCHF1通过促进RSET的泛素化和降解以及随后TFAM的转录，有助于乳腺癌的进展。下调MARCHF1可为治疗乳腺癌提供新的方向。
