Expression landscape of human stromal cells in preclinical trials involving chemotherapeutic and histone demethylase KDM4-targeting agents

Aging and age-related pathologies including multiple cancer types can be controlled by specifically targeting senescent cells, or more specifically, their hallmark feature, the senescence-associated secretory phenotype (SASP). Lysine methylation is one of the most common histone posttranslational modifications that regulate chromatin structure in mammalian cells. Changes in histone lysine methylation status have been observed during cancer progression, a consequence of dysregulation of histone lysine methyltransferases and/or their opposing demethylases. KDM4 (or JMJD2) encompasses demethylases that target histone H3 on lysines 9 and 36 sites. Frequently overexpressed in breast, colorectal, lung, prostate, and other tumor types and required for efficient cancer cell proliferation, KDM4 proteins represent novel drug targets. However, emerging studies are beginning to uncover the functional roles of KDM4 in epigenomic regulation during cellular senescence and organismal aging, thus providing a new angle to understand human aging and allowing expansion of the existing list of epigenetic targets, the drugs of which are currently limited to the pharmacological arsenal against DNA methyltransferases and histone deacetylases. Overall design: Examination of in vivo efficacy of a KDM4 inhibitor, ML324, when combined with conventional chemotherapy in reducing the SASP and promoting tumor regression under prelinical conditions. Experimental mice xenografted with human stromal cells and cancer cells were exposed to mitoxantrone (MIT), ML324 or MIT plus ML324, agents delivered via intraperitoneal injection. Drugs were administered in a metronomic manner, given biweekly from the 3rd week of a 8 week regimen.