Targeting Tudor Domain-Containing Methyltransferase SETDB1 in Breast Cancer: Molecular Mechanisms and Therapeutic Application
Abstract
Breast cancer is the most common cancer among women; there are an estimated 240,000 new cases of breast cancer diagnosed along with 40,000 deaths per year in the United States. The development of breast cancer is a complex, multifactorial process traditionally viewed as the stepwise accumulation of genetic alterations. However, there is mounting evidence that shows a different class of changes, termed epigenetic alterations, also plays fundamental roles in breast cancer initiation and progression. One of the most important epigenetic alterations is histone modifications that are regulated by histone-modifying enzymes. Notably, genetic and epigenetic alterations in cancer cells operate interdependently. For instance, systematic genome-wide analyses have uncovered that genes encoding for histone-modifying enzymes have a high frequency of genetic alterations in multiple tumor types, including breast cancer. Because histone-modifying enzymes are druggable and epigenetic alterations are reversible changes, pharmacologic targeting of histone-modifying enzymes is an attractive anti-cancer strategy for correcting the alteration of histone modifications and blocking breast cancer progression. Histone lysine methyltransferases (HMTs), a large class of histone-modifying enzymes that catalyze site-specific methylation of lysine residues on histones, play critical roles in epigenetic regulation. Dysregulation of HMTs can lead to imbalances of histone methylation, subsequently contributing to uncontrolled cell proliferation and cancer progression. We recently conducted a screen of 51 HMT genes in approximately 1,000 primary breast cancer samples, looking for genetic alterations of HMTs and their associations with breast cancer subtypes and clinical outcomes. We discovered that one of the HMTs, SETDB1 (SET domain, bifurcated 1; also known as ESET/KMT1E), is highly amplified across approximately 15% of all the human breast cancer samples. Notably, SETDB1 amplification was found in 31.5% of basal-like subtype samples, strongly implying its clinical importance. We have shown that inhibition of SETDB1 expression in SETDB1-gene-amplified breast cancer cells reduced tumor growth. Importantly, we uncovered that a unique functional domain, the Tudor domain, is critical for SETDB1’s role in cancer progression and growth. Furthermore, we are developing novel small molecule compounds that selectively inhibit SETDB1 Tudor activity. The objective of this application is to elucidate the fundamental mechanism of SETDB1 in driving breast cancer growth, and to establish it as a novel therapeutic target for aggressive basal breast cancers. The first specific aim will define the functional significance and molecular mechanism of Tudor domain in regulating SETDB1 recruitment and oncogenic functions in breast cancer. We will apply molecular and cellular approaches to elucidate biochemical binding properties of the SETDB1-Tudor domain, and then determine the importance of the Tudor domain in regulating SETDB1 functions to promote basal breast cancer growth and progression. In Specific Aim 2, we will investigate the impact of inhibiting SETDB1 Tudor function on breast cancer phenotypes in vitro and in mouse xenograft models. We will use genetic approaches and/or small-molecule compounds to measure the effects of inhibiting SETDB1 Tudor on blocking growth of breast cancer cells. We will then determine the impact of inhibiting SETDB1 Tudor function on the aggressive phenotype of breast cancer in mouse xenograft models. Upon completion of this study, we will: (1) establish SETDB1 as a critical player in promoting basal breast cancer growth and progression; (2) fundamentally understand the molecular mechanism of the histone-modifying enzyme SETDB1 activation in breast cancer; and (3) demonstrate the therapeutic potential of SETDB1 inhibitors for treating aggressive SETDB1-amplified breast cancer. This application directly addresses two Fiscal Year 2020 Breast
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110600
Entities
People
- Zeng-quan Yang
Organizations
- United States Army
- Wayne State University