Project Summary Cellular senescence is a tumor suppressive cell growth arrest triggered by inducers such as activation of oncogenes and chemotherapeutics. However, senescent cells are viable and may promote tumor progression and therapy relapse through secretion of factors such as cytokines, chemokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Thus, it would be ideal to enhance senescence-associated growth arrest while limiting SASP because this may lead to a durable therapeutic outcome. Notably, it remains to be determined whether silencing of proliferation genes and upregulation of SASP genes are coupled at the molecular level. Thus, the overall goal of this proposal is to investigate the mechanism that coordinates the silencing of proliferation genes and the upregulation of SASP genes during senescence and its implications in cancer and response to therapy. HMGB2 is a chromatin architecture protein that binds to DNA without sequence specificity. Our preliminary data suggest that HMGB2 orchestrates gene expression reprogramming during senescence by acting as a molecular switch. Specifically, loss of HMGB2 from genomic loci of proliferation genes contributes to their silencing. In contrast, HMGB2’s redistribution to SASP genes loci promotes their expression. Consistent with its role in senescence, HMGB2 is often upregulated in epithelial ovarian cancer (EOC) and its expression correlates with EOC progression. Further, expression of HMGB2 positively correlates with its target proliferation genes in EOCs. Based on these findings, our central hypothesis is that HMGB2 orchestrates gene expression reprogramming to regulate the switch from proliferation to senescence. We also hypothesize that HMGB2 contributes to EOC by suppressing senescence and promotes platinum-based therapy relapse by driving SASP. Accordingly, two specific aims are proposed: Aim 1: To elucidate the molecular mechanism by which HMGB2 regulates senescence;; and Aim 2: To determine the role of HMGB2 in EOC and therapy relapse. The proposed studies are highly novel because this is the first study to explore a novel molecular mechanism that orchestrates the silencing of proliferation-promoting genes and the upregulation of SASP genes during senescence. Thus, our studies are paradigm shifting in their potential to elucidate the molecular basis of gene expression reprogramming during senescence. The research proposed is of high impact because they will lay the critical foundation for ultimately developing novel strategies that harness the tumor-suppressive benefit of senescence, while limiting the detrimental aspects of SASP to ultimately achieve durable therapy outcome. Therefore, the current study will not only provide critical mechanistic insights into gene expression reprogramming during senescence, but will also have far-reaching implications for the development of senescence-based therapeutic...