Deciphering the genetic, transcriptional and epigenetic mechanisms driving cancer development

Abstract

Cancer remains a serious health challenge worldwide, with steadily increasing incidence and mortality. Although conventional treatments have improved outcomes for some patients, they often fall short in addressing metastatic or drug resistant cancers. Even with the rise of targeted and immune-based therapies, many cancers still lack effective treatment options due to the absence of suitable molecular targets. To address this, it is critical to deepen our perception of the cellular events that contribute to cancer development. This thesis focuses on unraveling cancer-driving mechanisms at the genetic, transcriptional, and epigenetic levels. Three molecular components are selected as key models: ATF3, a transcription factor; VPS72, an epigenetic regulator; and the CHD4 R975H mutant, a cancer-associated genetic variant. Through these studies, we aim to better understand how alterations in cellular information processing— ranging from DNA mutations to transcriptional control and chromatin regulation— promote carcinogenesis. In Chapter 2, we investigate the effect of ATF3 in liver cancer. Our experiments reveal that ATF3 functions as a repressor of tumor growth, particularly by limiting lipid production in cancer cells. We discover that ATF3 enhances the expression of SLC7A7, a transporter gene, which in turn restricts activation of the mTORC1 pathway—a vital mediator in cellular proliferation and metabolism. This ATF3 SLC7A7–mTORC1 cascade is shown to be a crucial mechanism restraining liver tumor development. Chapter 3 centers on VPS72, previously linked to cancer-promoting roles. Using liver cancer models, we demonstrate that VPS72 contributes to tumor growth by suppressing ATF3 and thereby indirectly activating mTORC1 signaling. Mechanistically, VPS72 modifies the chromatin landscape at the ATF3 gene locus by altering histone marks, including H3K4me1 and H2A.Z acetylation. When the interaction between VPS72 and the histone variant H2A.Z is disrupted, its tumor promoting effect is markedly reduced. These findings position VPS72 as a key chromatin regulator that influences cancer metabolism and growth through epigenetic suppression of ATF3. In Chapter 4, we examine the R975H mutation in CHD4, a gene involved in chromatin remodeling, in endometrial cancer. Our structural and functional studies indicate that this mutation impairs normal CHD4 function and leads to enhanced tumor formation. Additionally, R975H mutant is elucidated to increase cancer cell stemness and promote an immune-suppressive microenvironment by influencing macrophage polarization. Together, this work offers a comprehensive exploration of how disruptions in genetic sequences, transcriptional activity, and epigenetic regulation collectively shape cancer behavior. A recurring theme across all studies is the link between cellular metabolism, immune response, and chromatin control. These insights provide a basis for future research of tumorigenesis mechanisms and may support the development of more precise therapeutic strategies.