Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer

Abstract

BackgroundMTO1 and MRPL41 are nuclear-encoded mitochondrial genes encoding a mitochondrial tRNA-modifying enzyme and a mitochondrial ribosomal protein, respectively. Although both genes have been known to have potential roles in cancer, little is known about their molecular regulatory mechanism, particularly from an epigenetic approach. In this study, we aimed to address their epigenetic regulation through the estrogen receptor (ER) in breast cancer.MethodsDigital differential display (DDD) was conducted to identify mammary gland-specific gene candidates including MTO1 and MRPL41. Promoter CpG methylation and expression in breast cancer cell lines and tissues were examined by methylation-specific PCR and real time RT-PCR. Effect of estradiol (E2), tamoxifen, and trichostatin A (TSA) on gene expression was examined in ER + and ER- breast cancer cell lines. Chromatin immunoprecipitation and luciferase reporter assay were performed to identify binding and influencing of the ER to the promoters.ResultsExamination of both cancer tissues and cell lines revealed that the two genes showed an opposite expression pattern according to ER status; higher expression of MTO1 and MRPL41 in ER- and ER+ cancer types, respectively, and their expression levels were inversely correlated with promoter methylation. Tamoxifen, E2, and TSA upregulated MTO1 expression only in ER+ cells with no significant changes in ER- cells. However, these chemicals upregulated MRPL41 expression only in ER- cells without significant changes in ER+ cells, except for tamoxifen that induced downregulation. Chromatin immunoprecipitation and luciferase reporter assay identified binding and influencing of the ER to the promoters and the binding profiles were differentially regulated in ER+ and ER- cells.ConclusionsThese results indicate that different epigenetic status including promoter methylation and different responses through the ER are involved in the differential expression of MTO1 and MRPL41 in breast cancer.

Down-regulation of MRPS23 inhibits rat breast cancer proliferation and metastasis

“…If the expression of MRPS23 was inhibited, it could disturb the mitochondrial protein synthesis, affect function of mitochondrial and impair breast cancer cell proliferation. Several studies indicate that the ribosomal proteins and MRPs may be directly involved in the process of cancer proliferation and metastasis [ 25 , 26 ], which are dependent on the stimulated activity of p53 and p21 WAF1/CIP1 [ 16 , 27 , 28 ]. Yoo et al reported that the MRPL41 suppresses cell growth in association with p53, p27 Kip1 [ 15 ] and p21 WAF1/CIP1 [ 29 ].…”

“…Recent studies have examined the biological functions and the possible mechanisms of mitochondrial ribosomal proteins (MRPs) in cancers individually. Several evidence have shown that MRPs are involved in cell proliferation and mitochondrial apoptosis through the p21 WAF1/CIP1 [ 13 ], p53 [ 14 – 16 ] and cytochrome c (Cyt c) -mediated pathway [ 17 ]. p21 WAF1/CIP1 may be regulated through either p53-dependent [ 18 ] or p53-independent mechanism [ 19 ].…”

MTO1 Worked as a Modifier in the Aminoglycosides Sensitivity of Yeast Carrying a Mitochondrial 15S rRNA C1477G Mutation

“…Another study has shown that MTO1 mutations are associated with a mitochondrial disorder characterized by hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency [ 16 ]. Recently, the MTO1 gene was also reported to play a role in breast cancer tissues and cells [ 17 ]. This indicates that the function of the MTO1 gene may be more complicated than previously considered.…”

Mitochondrial Proteomic and Molecular Network Alterations in Human Ovarian Cancers

“…Second, mitochondrial ribosomal proteinencoding genes might be the anti-oncogenes to serve as new biomarkers and therapeutic targets. For example, bcl-2-interacting mitochondrial ribosomal protein L41 (MRPL41) is differentially expressed in carcinomas to associate with various epigenetic states [8]. Mitochondrial ribosomal protein S23 (MRPS23) is involved in cancer cell proliferation, which might serve as the therapeutic target [9].…”