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Investigation of lncRNA Isoform-Specific Alterations and MYC Acetylation in Cancer

  • Author(s): Hamilton, Michael
  • Advisor(s): Martinez, Ernest
  • et al.
Abstract

The events leading to the development of cancer often involve a series of sequential molecular derailments. The complexities of these derailments are frequently specific not only to the type of cancer, but can also be specific to an individual tumor. However, despite these challenges, investigations characterizing the global or universal aberrations seen in human cancers have provided many effective therapeutic strategies to the combat human malignancies. The current dissertation focuses on two neglected areas of study in the cancer biology field, the study of lncRNA isoform-specific alterations and the post-translational modifications of the critically important MYC oncoprotein in cancer.

In the beginning chapters of this dissertation, we explore isoform-specific alterations in a subtype of renal cell carcinomas, known as clear cell renal cell carcinoma (ccRCC). ccRCC is one of the most prevalent cancers within the United States, and can be particularly difficult to treat with conventional therapies. As such, new therapeutics strategies are needed to treat ccRCC in its later stages of the disease. ccRCC has been shown to have severe aberrant RNA production and processing, lending itself as a prime candidate to explore isoform-specific alterations. Furthermore, using new computational methods, we identified previously uncharacterized events of differential transcript and usage in ccRCC implicating several novel genes in the pathology. Discovered within these transcriptomic analyses was a long non-coding RNA, referred to as HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1), which was found to be specifically downregulated in ccRCC and regulates key genes involved in the hypoxia pathway. In chapter 3, we investigate HOTAIRM1 further examining its function in ccRCC and its role in kidney cell differentiation and maintenance.

In the last two chapters, we discuss and evaluate the effects of two disparate levels of MYC regulation. First, we discuss the complex nature of the interplay between MYC expression and numerous lncRNAs, in what is referred to as the lncRNA-MYC network. In this review, we reveal the breadth of the complexities of how MYC is regulated by lncRNAs and how MYC regulates its oncogenic function through the use of lncRNAs. Finally, with the development of innovative transgenic cell lines, expressing different mutant forms of MYC, we demonstrate that different acetylation states of MYC can have gene-selective effects and consequently alter different molecular pathways.

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