Metabolic reprogramming is a hallmark of cancer that plays an essential role in tumor initiation and progression. Glutamine metabolism, due to its diverse role in central metabolism, signaling and epigenetics, has become the forefront of cancer metabolism research. In addition to the Warburg’s effect, emerging evidence reveals that the “glutamine addiction” in human tumors play an important role in both tumorigenesis and therapeutic response. With enhanced glutamine uptake and poor vascularization at the tumor sites, it appears that most solid tumors will experience some degree of glutamine deficiency similar to the low oxygen conditions or hypoxia. While the role hypoxia in tumor biology is well established, the impact of intratumoral glutamine deficiency on cancer progression and therapeutic response remains largely unknown. This dissertation will explore potential effects of glutamine deficiency on various cellular processes in malignant cells including DNA damage response pathway, epigenetic reprogramming, oncogenic signaling, and drug response.

In chapter 1, I summarize recent progress in understanding the glutamine addiction in cancer and highlight clinical opportunities in targeting glutamine metabolism.

In chapter 2, we investigate the role of tumor-associated mutant p53 in cellular response to glutamine deprivation. We demonstrate that mutant p53 plays a major role in cellular adaptation to glutamine deprivation through the upregulation of pro-survival genes but not pro-death genes.

In chapter 3, we examine the crosstalk between glutamine metabolism and DNA damage repair pathway. We provide mechanistic insights by which glutamine deficiency inhibits the DNA repair activity of the ALKBH enzymes, leading to an accumulation of DNA alkylation damage and thereby increasing cellular sensitivity to alkylating agents.

In chapter 4, we study the effect of glutamine metabolism on oncogenic Wnt signaling pathway and colorectal cancer development. We reveal that glutamine/alpha-ketoglutarate axis through epigenetic modulations is a critical regulator of Wnt signaling and cellular differentiation in colon cancer. We further explore the potential impact of glutamine starvation on the adeno-carcinoma transition in colon cancer progression and the therapeutic potential of alpha ketoglutarate supplementation in colon cancer treatment.

In chapter 5, I discuss recent progress on the crosstalk between metabolism and epigenetic regulation in cancer. I will further discuss remaining questions, future directions and clinical implications derived from these findings.

Tumors reprogram pathways of nutrient acquisition and metabolism to meet their bioenergetic needs and fast proliferation. Glutamine, a non-essential amino acid, was shown to contribute to several core metabolic pathways, as well as epigenetic modifications, in proliferating tumor cells. However, neovasculature development in growing tumors fail to deliver oxygen and key nutrients, such as glutamine, to regions of solid tumors. Concurrently, increased glutamine utilization in cancer cells often lead to its depletion. Similar to hypoxia, cancer cells initiate remodeling of metabolism and gene expression to adapt to these periods of glutamine deprivation.

This dissertation will present recent understanding of nutrient stress in the microenvironment, with special focus on glutamine metabolism, and the role of glutamine metabolism in supporting deregulated epigenetics in cancer. Specifically, we demonstrate a potential survival mechanism mediated by an IKKβ-p53 signaling axis in cancer upon glutamine deprivation. We found that, upon glutamine depletion, IKKβ can directly phosphorylate p53 on Serine 392, which activates it, independent of the NF-κB pathway. The newly identified IKKβ-p53 signaling axis is necessary in mediating survival through the upregulation of p53 downstream genes.

Finally, we investigate the therapeutic potential of using dietary glutamine supplementation to inhibit tumor growth by exploiting the protean role of glutamine in cancer metabolism and epigenetics. Our results indicate glutamine supplementation in melanoma tumors downregulates the expression of oncogenes via epigenetic reprogramming and cooperates with targeted therapies. These results further solidify the connection between metabolites and epigenetic changes that can be detrimental to cancer cells that adapted to glutamine deprivation in their microenvironment.