A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma

Royce W. Zhou, Jia Xu, Tiphaine C. Martin, Alexis L. Zachem, John He, Sait Ozturk, Deniz Demircioglu, Ankita Bansal, Andrew P. Trotta, Bruno Giotti, Berkley Gryder, Yao Shen, Xuewei Wu, Saul Carcamo, Kaitlyn Bosch, Benjamin Hopkins, Alexander Tsankov, Randolph Steinhagen, Drew R. Jones, John AsaraJerry E. Chipuk, Rachel Brody, Steven Itzkowitz, Iok In Christine Chio, Dan Hasson, Emily Bernstein, Ramon E. Parsons

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number6041
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

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