Identification and Characterization of Epigenetic Regulators of Breast Cancer Metastasis
Date of Award
Doctor of Philosophy (PhD)
Cancer metastasis remains a major clinical challenge for cancer treatment. It is therefore crucial to understand how cancer cells establish and maintain their metastatic traits. Emerging evidence suggests that key steps of metastasis are controlled by reversible epigenetic mechanisms, which can be targeted to prevent and treat the metastatic disease. Although a variety of epigenetic mechanisms were identified to regulate cancer metastasis, including the well-studied DNA methylation and histone modifications, there are very few epigenetic drugs for cancer treatment and currently none of them was approved specifically for metastasis. Thus, we aim to uncover novel epigenetic regulators and identify the underlying mechanism to develop potential therapeutic strategies against breast cancer metastasis. We have performed an in vivo loss-of-function epigenetic screen to identify actionable epigenetic drivers within the progression of breast cancer metastasis. We identified several strong hits for breast cancer metastasis to the lungs or the brain. Some of the discovered hits were organ specific, while some hits were shared between the lung and brain screen such as NAT10 and UBE2I. In addition, the screen was able to reproduce reported epigenetic targets that have roles in metastasis. Thus, our screening strategy provides an efficient way to understand the complexity of metastasis. While NAT10 has been implicated in some cancer types, its function in breast cancer is unclear. We therefore focus on elucidating the role of NAT10 in breast cancer metastasis. We found NAT10 silencing significantly impaired the tumorigenic and metastasis capability of breast cancer cells. Mechanistically, we discovered that NAT10 regulates breast cancer cell growth through its RNA helicase activity but not its acetyltransferase activity. Biologically, NAT10 regulates the expression of several cell cycle regulators and global translation. We will further dissect how the RNA helicase activity of NAT10 contributes to the cell growth phenotype and proposed potential NAT10 targeting strategy. WDR5 is another strong hit identified from breast cancer lung metastasis screen. Its oncogenic function has been reported in a variety of cancers, however, most of these finding suggested a methyltransferase-dependent mechanism. In our study, we showed WDR5 silencing significantly impaired breast cancer cell growth and metastasis. With transcriptomic profiling, we discovered that WDR5 regulates ribosomal gene expression to promote global translation and thereby promote cell growth. Importantly, we found such mechanism is independent of the KMT2 complex components, which suggests an KMT2 enzymatic activity-independent regulation of WDR5. Consistently, either WDR5 inhibitor or WDR5 degrader was able to reproduce the growth inhibition phenotype of WDR5 silencing in breast cancer. Lastly, combination of WDR5 and mTOR inhibition provides more potent suppression of breast cancer growth and an additional therapeutic option for future breast cancer treatments.
Chen, Jocelyn Fang-Yi, "Identification and Characterization of Epigenetic Regulators of Breast Cancer Metastasis" (2022). Yale Graduate School of Arts and Sciences Dissertations. 464.