Determining the Role of HRP2 in Oncogenic Senescence

Cellular senescence is a tumor-suppressor mechanism that prevents the proliferation of cancerous cells by inducing a state of permanent cell cycle arrest. Common characteristics of senescent cells include abnormal cell morphology and increased expression of the cyclin-dependent kinase inhibitor p16. Elevated p16 expression is facilitated by the presence of senescence-associated heterochromatin foci (SAHF), which are formed in part by the HP1 epigenetic pathway. We have previously identified hepatoma-derived growth factor-related protein 2 (HRP2) as a novel protein of the HP1 pathway; however, little is known about its function as an epigenetic regulator. To better understand the role of HRP2 within the HP1 pathway, we investigated whether HRP2 contributes to the pathway’s senescence-promoting behavior. We found that exogenous expression of HRP2 promotes a senescent-like phenotype in the triple-negative breast cancer cell line MDA-MB-231, as well as the prostate cancer cell line PC3. Wound-healing analysis demonstrated that HRP2 infection inhibits motility of MDA-MB-231 cells, but not PC3 cells. Using CRISPR-dCas9 technology to modulate endogenous HRP2 expression levels, we observed that endogenous HRP2 expression is positively correlated with p16 expression in MDA-MB-231 cells. Taken together, these findings indicate that in certain cell lines, HRP2 acts within the HP1 pathway to form SAHF, promoting p16 expression and driving cells into premature senescence. A better understanding of the mechanistic function of HRP2 as a chromatin modulator may clarify the processes of this cellular stress-response pathway and lead to the development of novel therapeutics to treat diseases associated with its dysregulation, such as cancer.Bachelor of Scienc