Research

Genetic mutations are known cancer drivers, but not all patients harbor sufficient driver mutations to account for the onset and progression of the disease. There also exist cancers such as pediatric tumors and several liquid cancers that carry very few genetic alterations, highlighting the need for deeper understanding of non-genetic events that are equally potent to drive tumorigenesis. The role of RNA aberrations in cancer has recently come to light and paves avenues for discovery of mechanisms critical for malignant transformation. Novel therapeutic approaches that target RNA have shown clinical success, resulting in several FDA approved drugs and dozens of clinical trials for a variety human disorders and cancers.

During transcription, precursor RNAs undergo a series of RNA processing events to form mature mRNAs. The 3' end of mRNA is generated by the cleavage of mRNA at a polyadenylation site, followed by the addition of a polyadenosine tail. As most human genes contain multiple polyadenylation signals, these sites can be used in a condition-dependent manner to produce different RNA transcripts. This phenomenon is termed “alternative cleavage and polyadenylation (APA)”, forming an evolutionarily conserved layer of gene regulation.

When APA occurs in the 3'-untranslated region (3'UTR) of a gene (termed 3'-APA), it generates mRNA isoforms that carry the same coding sequences but differ in their 3'UTRs. These isoforms contain different regulatory elements that determine each RNA’s fate (e. g. stability, localization) and affect protein translation and protein-protein interaction. As such, 3'-APA increases transcriptome and proteome complexity in cells. Cancer cells employ this mechanism to alter protein functions and gain oncogenic properties (Lee et al., 2019, shown in the figure on the right side). When polyadenylation signals in introns are recognized (termed intronic APA), cells generate truncated mRNA isoforms. Cancer cells are able to utilize intronic polyadenylation to inactivate tumor suppressor genes and promote cell survival (Lee and Singh, et al., 2018). Thus, intronic APA phenocopies the outcome of genetic truncating mutations to abolish normal gene functions in cells.

APA is widespread in both healthy and diseased cells. However, its functional significance is largely underappreciated and the underlying mechanisms by which APA occurs are poorly studied. Our laboratory uses genetic, molecular and cell biological, and biochemical approaches to understand how cancer cells exploit APA to manipulate cancer-relevant genes at the level of mRNA but not DNA to impact the biology of cancer cells and promote disease development and progression. We also explore the regulatory networks that modulate APA formation. We hope to provide new treatment strategies to tackle cancer.