Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression

摘要

Age is a major risk factor for the development of cancer. Senescent fibroblasts, which accumulate with age, secrete pro-tumorigenic factors collectively referred to as the senescence-associated secretory phenotype (SASP). Here we examined the molecular mechanisms that control SASP activation, focusing on the known SASP factor osteopontin (OPN). We found that expression of the canonical SASP members IL6 and IL8, but not OPN, were dependent upon a persistent DNA damage response (DDR) as evidenced by ATM and NF-κB activation. Treatment with several histone deacetylase (HDAC) inhibitors robustly activated SASP in the absence of DNA breaks, suggesting that DDR-dependent SASP activation occurs in response to chromatin remodeling rather than physical breaks in DNA. In the setting of histone deacetylase inhibition, IL6 and IL8 expression remained dependent upon ATM and NF-κB, while OPN expression remained independent of these factors. Further analysis revealed that HDAC1 was sufficient to induce OPN expression, which is interesting given that loss of HDAC1 expression correlates with increased OPN expression within the stromal compartment of invasive breast cancers. Importantly, fibroblasts treated with HDAC inhibitors promoted tumor growth in vivo. Our findings therefore indicate that HDAC modulation plays an important role in stromal cell activation, with important implications for the use of HDAC inhibitors in the treatment of cancer.