Citations 2
Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
Song, Shuling, Jiang, Jing , Kirkland, James L. , Sun, Yu , Tchkonia, Tamara, Sun, Yu , Tchkonia, Tamar
Advanced Science | October 19, 2020 | Volume: 7 | Issue: 23 | Pages: No page available
Abstract Aging is a physiological decline in both structural homeostasis and functional integrity, progressively affecting organismal health. A major hallmark of aging is the accumulation of senescent cells, which have entered a state of irreversible cell cycle arrest after experiencing inherent or environmental stresses. Although cellular senescence is essential in several physiological events, it plays a detrimental role in a large array of age‐related pathologies. Recent biomedical advances in specifically targeting senescent cells to improve healthy aging, or alternatively, postpone natural aging and age‐related diseases, a strategy termed senotherapy, have attracted substantial interest in both scientific and medical communities. Challenges for aging research are highlighted and potential avenues that can be leveraged for therapeutic interventions to control aging and age‐related disorders in the current era of precision medicine.
KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype
Zhang, Boyi , Long, Qilai , Wu, Shanshan , Song, Shuling, Xu, Qixia, Liu, Han , Qian, Min , Ren, Xiaohui , Jiang, Jing , Fu, Qiang , Guo, Jianming , Chang, Xing, Campisi, Judith , Kirkland, James L. , Qian, Min, Fu, Qiang, Zhang, Xiaoling , Lam, Eric W.‐F. , Sun, Yu
No container title available | August 17, 2020 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation, including epigenetic decoration of chromatin structure and functional modulation of bioactive components. Here we report that expression of the histone H3-specific demethylase KDM4 is upregulated in human stromal cells upon cellular senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation are correlated with adverse survival of cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq and expression profiling through RNA-seq reveal extensive reorganization of chromosomes and spatiotemporal reprogramming of the transcriptomic landscape, events responsible for development of the senescence-associated secretory phenotype (SASP). Selectively targeting KDM4 dampens the SASP of senescent stromal cells and enhances the apoptotic index of cancer cells in the treatment-damaged tumor microenvironment (TME), together prolonging overall survival of experimental animals. Our study supports the dynamic change of H3K9/H3K36 methylation marks during cellular senescence, identifies an unusually permissive chromatin state, unmasks KDM4 as a key modulator of the SASP, and presents a novel therapeutic avenue to manipulate cellular senescence and curtail age-related pathologies.