Unraveling the impact of KDM6A loss on colon and bladder cancers: an in vitro and in vivo analysis

Abstract

Due to the fact that over half of human cancers are known to contain perturbed epigenetic signaling, it is crucial to understand the biology of key epigenetic regulators. This dissertation investigates the multifaceted role of the histone demethylase KDM6A in cancer, with a focus on its impact on colon and bladder cancers. Chapter 1 provides a comprehensive background on epigenetic signaling, emphasizing the critical role of histone modifications in both development and disease. In reviewing the large body of KDM6A literature from the last two decades, this chapter also delves into the dual nature of KDM6A, which can act as both a tumor suppressor and an oncogene depending on the tissue context. Chapter 2 explores a newly found insensitivity to KDM6A loss in a murine colorectal cancer model, revealing that KDM6A deletion does not confer proliferative advantages in vitro or improve tumor growth and immune evasion in vivo, contradicting existing but limited studies of KDM6A in colorectal cancer. Chapter 3 focuses on generating and characterizing cancer models with truncated KDM6A, demonstrating that truncated Kdm6a in murine cancer models leads to reduced proliferation and distinct transcriptional profiles. Finally, Chapter 4 summarizes these findings, discussing future research directions such as the establishment of murine models of catalytically inactive KDM6A and the exploration of its therapeutic potential. This work highlights the complex interplay between KDM6A's enzyme-dependent and enzyme-independent activities and underscores its significant yet context-specific role in cancer biology.