Methyltransferase METTL4 Mediates Mitochondrial Function in Breast Cancer: Oncogenic Role and Therapeutic Potential
Abstract
Breast cancer is the most common cancer among women, with more than 240,000 new cases diagnosed and 40,000 deaths in the United States per year. Recent molecular profiling of breast cancer has identified distinct subtypes with prognostic and therapeutic implications; the subtype of basal-like or triple-negative is particularly aggressive and accounts for a disproportionate number of breast cancer deaths. The treatment for basal-like breast cancer consists of standard chemotherapy regimens as no effective molecularly targeted therapies have been developed. Thus, there remains a significant need to elucidate what drives breast cancer, particularly basal-like breast cancer growth, and develop new classes of molecules that target heretofore unexplored cellular mechanisms so that tumors not responsive to a particular treatment might be responsive to these new routes of therapy. RNA serves as a connecting link for genetic information passing from DNA to protein. Gene expression is known to be extensively and dynamically altered by a variety of reversible RNA modifications including N6-methyladenosine (m6A). The biological significance of m6A has only recently emerged due to the identification of a set of RNA modifier factors that regulate gene expression through these modifications. However, little attention has been given to understanding roles of these RNA modifiers in cancer initiation and progression and about the molecular mechanism of these modifiers in regulating oncogenic and metabolic programs in breast cancer. To determine the genomic landscape and clinical significance of RNA modifiers in breast cancer, we recently conducted a metagenomic analysis of 80 RNA modifiers in approximately 3000 primary breast cancer samples and cancer cell lines. We discovered several RNA modifiers that were significantly overexpressed in a set of breast cancers. Notably, alteration of methyltransferase-like 4 (METTL4) was associated with aggressive characteristics of breast cancer. Interestingly, our preliminary studies revealed that METTL4 protein is predominantly localized in the mitochondria, which are the powerhouses of the cell. Dysregulation of mitochondrial metabolism is implicated in a wide range of rare and common human diseases, including breast cancer. We propose that suppressing METTL4 methyltransferase activity would inhibit METTL4-mediated oncogenic programming on mitochondria and subsequently suppresses the aggressive phenotypes of basal-like breast cancer. The objective of this application is to elucidate the fundamental mechanism of METTL4 in driving breast cancer growth and to establish it as a novel therapeutic target for aggressive basal-like breast cancers. The first specific aim will determine the impact of METTL4 overexpression on aggressive phenotypes of breast cancer in vitro and in mouse cancer xenograft models. We will apply molecular and cellular approaches to elucidate the biological role of methyltransferase METTL4 in breast cancer and investigate the impact of inhibiting METTL4 function on breast cancer growth and aggressiveness in vitro and in xenograft models. In Specific Aim 2, we will investigate the molecular mechanism by which METTL4 alters mitochondrial RNA metabolism and bioenergetics in breast cancer. We will determine how METTL4 affects mitochondrial RNA metabolism in breast cancer by using a series of RNA immunoprecipitations, in vitro biochemical methylation, and molecular biological assays in breast cancer cells. We will then determine how METTL4 inhibition and overexpression affect mitochondrial bioenergetics in METTL4 breast cancer cell models. Upon completion of this study, we will: (1) establish METTL4 as a critical player in promoting breast cancer growth and progression in a set of aggressive breast cancers; (2) fundamentally understand the molecular mechanism mediated by METTL4 in mitochondrial RNA metabolism and bioenergetics of breast cancer; and (3) demonstrate the t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710337
Entities
People
- Zeng-quan Yang
Organizations
- United States Army
- Wayne State University