Abstract 2031: The <i>PERK</i> arm of the unfolded protein response induces <i>CXCL8</i> and <i>CCL20</i> through C/EBPδ
Authors: Dipak Kumar Poria, Namratha Sheshadri, Shikha Sharan, Esta Sterneck
Journal: Cancer Research (2021)

Abstract Cancer cells often experience endoplasmic reticulum (ER) stress due to either activated oncogenes, microenvironmental conditions or therapeutic interventions. ER stress initiates an adaptive unfolded protein response (UPR) program, mediated by PERK, IRE1 and ATF6 transmembrane sensors, which alleviates the stress and promotes cells survival. However, if unmitigated, the UPR proceeds to initiation of cell death. Cancer cells often usurp the UPR pathways that contribute to cell survival and metastasis through intra- and intercellular mechanisms. Intracellular mechanisms of cellular adaptation are well-characterized; however, the intercellular consequences of ER stress are less understood. Here, we show that in cell lines representing melanoma, breast and prostate cancer, the transcription factor C/EBPδ (CEBPD) is an early ER stress response factor that is induced by the PERK arm of the UPR. CEBPD induction occurs in part through activation of PERK-mediated non-canonical JAK/STAT3 signaling. Transcriptional profiling in MDA-MB-435 melanoma cells revealed that C/EBPδ supports the expression of genes involved in cell intrinsic adaptations such as chaperones, components of ER associated degradation, and apoptosis inhibitors. In addition, C/EBPδ promotes expression of the inflammatory mediators CXCL8 and CCL20, which are known to modulate the tumor microenvironment through the receptors present on various host cells. Depletion of CEBPD by siRNA or inhibition of PERK kinase reduced CXCL8 and CCL20 transcripts and secreted proteins upon ER stress induction by thapsigargin. Bioinformatic analysis and the ENCODE ChIP-seq data suggest direct interaction of C/EBPδ with CXCL8 and CCL20 promoter/enhancer, indicative of direct transcriptional activation of the genes. Indeed, ectopic expression of C/EBPδ, but not a mutant lacking the transactivation domain, was sufficient to induced CXCL8 and CCL20 transcription in HEK293 cells in the absence of ER stress. Consistent with these results, conditioned media from ER-stressed MDA-MB-435 cells induced the gene expression of proinflammatory cytokines IL-6, IL-12, TNFα and IL-1RA in HL-60 promyelocytic cells while suppressing IL-10 expression. Taken together, these data show that the PERK arm of the UPR activates JAK/STAT3 pathway to induce expression of C/EBPδ and thereby enhance secretion of immunomodulators and transmit UPR-induced inflammatory signals to immune cells in the tumor microenvironment. This pathway may contribute to the overall outcome of the UPR on cancer cell survival, metastasis and response to anticancer therapies. Citation Format: Dipak Kumar Poria, Namratha Sheshadri, Shikha Sharan, Esta Sterneck. The PERK arm of the unfolded protein response induces CXCL8 and CCL20 through C/EBPδ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2031.