Tao Lu

By Han Wei, Lakshmi Prabhu, Antja-Voy Hartley, Matthew Martin, Emily Sun, Guanglong Jiang, Yunlong Liu and Tao Lu

The nuclear factor κB (NF-κB) is one of the most pivotal transcription factors in mammalian cells. In many pathologies NF-κB is activated abnormally. This contributes to the development of various disorders such as cancer, acute kidney injury, lung disease, chronic inflammatory diseases, cardiovascular disease, and diabetes. This book chapter focuses on how methylation of NF-κB regulates its target genes differentially. The knowledge from this chapter will provide scientific strategies for innovative therapeutic intervention of NF-κB in a wide range of diseases.

Part of the book: Gene Expression and Regulation in Mammalian Cells

By Antja-Voy Hartley, Matthew Martin and Tao Lu

Colorectal cancer (CRC) is one of the most aggressive cancers worldwide and is known to develop through a stepwise process involving the accumulation of several genetic and epigenetic alterations. Furthermore, numerous studies have highlighted the significant role that certain epigenetic enzymes play in CRC pathogenesis, particularly those that govern chromatin components in the promoter regions of tumor suppressors and oncogenes. Here, we delineate the relationship between CRC-associated epigenetic marks, their modifying enzymes, and the classification of CRC into distinct molecular pathways or subtypes. Moreover, we discuss some of the most prominent methyltransferases, demethylases, acetyltransferases, and deacetylases, which have been targeted for preclinical and clinical CRC treatment. Notably, inhibitors against these epigenetic enzymes are a promising new class of anticancer drugs, with several obtaining Food and Drug Administration (FDA) approval for the treatment of blood and solid tumors. By highlighting the epigenetic molecular pathways leading to CRC development as well as providing an update on current CRC epigenetic therapies, this chapter sheds fresh insight into new and emerging avenues for future therapeutics.

Part of the book: Advances in the Molecular Understanding of Colorectal Cancer

By Matthew Martin, Antja-Voy Hartley, Jiamin Jin, Mengyao Sun and Tao Lu

The proinflammatory transcription factor nuclear factor-κB (NF-κB) has emerged as a central player in inflammatory responses and tumor development since its discovery three decades ago. In general, aberrant NF-κB activity plays a critical role in tumorigenesis and acquired resistance to chemotherapy. This aberrant NF-κB activity frequently involves several post-translational modifications of NF-κB, including phosphorylation. In this chapter, we will specifically cover the phosphorylation sites reported on the p65 subunit of NF-κB and their relationship to cancer. Importantly, phosphorylation is catalyzed by different kinases using adenosine triphosphate (ATP) as the phosphorus donor. These kinases are frequently hyperactive in cancers and thus may serve as potential therapeutic targets to treat different cancers.

Part of the book: Adenosine Triphosphate in Health and Disease

By Aishat A. Motolani, Mengyao Sun, Matthew Martin, Steven Sun and Tao Lu

Cancer is the second leading cause of mortality in the United States. There are several therapeutic regimens employed to mitigate the mortality rate of cancer. This includes the use of chemotherapy, radiation, immunotherapy, and precision medicine/targeted therapy. Targeted therapy involves the use of drugs that target a specific pathway or biomolecule compromised in cancer for cancer treatment. Aberrant expression of epigenetic enzymes has been well documented for their contribution in driving tumorigenesis and other cancer hallmarks. Hence, there is an urgent need for novel drug discovery and development in epigenetics to help combat various cancer morbidities. Herein, we review the roles and consequences of dysregulated function of several epigenetic enzymes, with a focus on histone methyltransferases (HMTs). Additionally, we discussed the current efforts made in the development of small molecule inhibitors for a few representative HMTs implicated in different cancers. Furthermore, the common screening assays used in discovering potent small molecule inhibitors were also detailed in this chapter. Overall, this book chapter highlights the significance of targeting HMTs in different cancers and the clinical application potentials/limitations faced by the developed or emerging small molecule inhibitors of HMTs for the purpose of cancer therapy.

Part of the book: Translational Research in Cancer

By Aishat Motolani, Matthew Martin, Steven Sun and Tao Lu

Drug discovery is an exciting yet highly costly endeavor. In the United States, developing a new prescription medicine that gains marketing approval takes near a decade and costs drugmakers for near 3 billion. More challengingly, the success rate of a compound entering phase I trials is just slightly under 10%. Because of these mounting hurdles, repurposing market approved drugs to new clinical indications has been a new trend on the rise. Another merit to this approach is the already confirmed toxicity profiles of the drugs and their possession of drug-like features. Thus, repurposed drugs can reach the market approved stage in a much faster, cheaper, and more efficient way. Notably, epigenetic enzymes play a critical role in the etiology and progression of different diseases. Researchers are now assessing the possibilities of using market approved drugs to target epigenetic enzymes as a novel strategy to curtail disease progression. Thus, in this book chapter, we will provide an outlook on repurposing market drugs to target epigenetic enzymes in various diseases. Consequently, this book chapter will not only provide the readers with current knowledge in this specific field, but also will shed light on the pathway forward for repurposing market drugs to target epigenetic enzymes in human diseases.

Part of the book: Drug Repurposing