MARCHF1 promotes breast cancer through accelerating REST ubiquitylation and following TFAM transcription.

Abstract

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.