作者
Royce Zhou,Jia Xu,Tiphaine Martin,Alexis L. Zachem,John Cijiang He,Sait Öztürk,Deniz Demircioğlu,Ankita Bansal,Andrew Trotta,Bruno Giotti,Berkley E. Gryder,Yao Shen,Xuewei Wu,Saul Carcamo,Kaitlyn Bosch,Benjamin D. Hopkins,Alexander M. Tsankov,Randolph M. Steinhagen,Drew R. Jones,John M. Asara,Jerry E. Chipuk,Rachel Brody,Steven H. Itzkowitz,Iok In Christine Chio,Dan Hasson,Emily Bernstein,Ramon Parsons
摘要
Tumors exhibit enhancer reprogramming compared to normal tissue. The etiology is largely attributed to cell-intrinsic genomic alterations. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon, we find divergent epigenetic landscapes between CRC tumors and cell lines. Intriguingly, this phenomenon extends to highly recurrent aberrant super-enhancers gained in CRC over normal. We find one such super-enhancer activated in epithelial cancer cells due to surrounding inflammation in the tumor microenvironment. We restore this super-enhancer and its expressed gene, PDZK1IP1, following treatment with cytokines or xenotransplantation into nude mice, thus demonstrating cell-extrinsic etiology. We demonstrate mechanistically that PDZK1IP1 enhances the reductive capacity CRC cancer cells via the pentose phosphate pathway. We show this activation enables efficient growth under oxidative conditions, challenging the previous notion that PDZK1IP1 acts as a tumor suppressor in CRC. Collectively, these observations highlight the significance of epigenomic profiling on primary specimens.