Pancreatic ductal adenocarcinoma (PDAC) is characterized by two molecular subtypes, of which the basal-like subtype is associated with the worst survival and is highly resistant to first-line chemotherapy. We previously reported that keratin 17 (K17), a component of the molecular signature of the basal-like subtype, is a negative prognostic and predictive biomarker, whose overexpression results in chemoresistance and shortened patient survival. Here, we aimed to uncover the mechanistic role of K17 in driving cancer aggression and explore the therapeutic opportunities in K17-expressing PDAC. Beyond its role as a cytoskeletal protein, K17 can solubilize from the filamentous form and translocate into the nucleus, where it impacts multiple cellular properties. Previous reports suggest that nuclear K17 regulates cell-cycle progression and gene expression. However, the detailed mechanisms through which K17 modulates gene expression remains unexplored. Through domain-prediction analyses, we identified a novel chromatin-remodeling (SANT) domain in K17 that may interact with histones to regulate chromatin structure. The assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed that K17 positive cells had comparably accessible regions relative to K17 negative cells. However, the deletion of the K17 SANT domain (dSANT) decreased chromatin accessibility, suggesting that nuclear K17 impacts chromatin structure via the SANT domain. With RNA sequencing (RNA-seq) pathway enrichment analysis, we found that K17 positive cells had differential expressed genes that are associated with cell signaling, immune regulation, and metabolic pathways. More specifically, by comparing wild type K17 and dSANT K17-expressing cells, we found that the SANT domain impacts a wide variety of immune regulatory pathways, many of which affect the tumor microenvironment. We are now performing chromatin immunoprecipitation sequencing (ChIP-seq) with acetylation of lysine 27 on histone H3 protein subunit (H3K27ac), to reveal differential bindings that are impacted by K17 and the SANT domain. Importantly, mice bearing orthotopic xenografts of PDACs with K17-SANT deletion showed survival comparable to those with K17 negative tumors and had significantly longer survival than those with wild-type K17. In summary, we identified a novel chromatin remodeling domain in K17 that could be explored as a target for the development of a biomarker-based treatment for PDAC.

Citation Format: Chun-Hao Pan, Robert Tseng, Simon J. Hogg, Gabriella Baraks, Cindy V. Leiton, Lucia Roa-Peña, Natalia Marchenko, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos. A novel chromatin remodeling domain of keratin 17 regulates transcription and promotes tumor aggression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-048.