DR1 activates histone gene expression to maintain pancreatic cancer cell survival through the ATAC complex.

Pancreatic ductal adenocarcinoma (PDAC) is the most malignant cancer and is characterized by short survival and limited treatment options. Epigenetic dysregulation is a defining feature of tumorigenesis but remains elusive in PDAC. Here, we identified DR1 as a vulnerability in PDAC. Loss of DR1 inhibited PDAC cell survival through repressing cell cycle. Mechanistically, DR1 recruited the ATAC complex to histone promoter regions to acetylate H3K9 and subsequently activate the expression of histone genes, ultimately promoting cell cycle and maintaining PDAC cell survival. Moreover, we uncovered a positive correlation between histone gene expression and the survival of patients with PDAC. In conclusion, our findings underscore the pivotal role of DR1 in the regulation of histone genes through the ATAC complex, providing a potential therapeutic target for PDAC.