While microclimates shape environments along coastlines and urban jungles, this phenomenon isn’t restricted to macroscopic landscapes; now, a new study provides evidence that inflammatory signaling from the tumor microenvironment (TME) alters the epigenetic landscape by inducing the formation of a super-enhancer (SE) that drives tumorigenesis.
An environmentally-friendly team led by Ramon E. Parsons (Icahn School of Medicine at Mount Sinai) asked whether the local TME can influence the existence of H3K27ac-modified SEs in colorectal cancer CRC tumor samples and cell lines. This green epigenetic team hoped to determine whether these changes functionally benefited tumor growth, given that SE landscape dysregulation often occurs in cancer.
Let’s walk our way through all the exciting data conjured up by Zhou and colleagues:
- Comparing tumors and healthy tissue using H3K27ac ChIP-seq identifies 12 tumor-dysregulated SEs
- Cell lines display differing H3K27ac signals compared to tumors, suggesting the induction of SEs by the TME
- An SE encompassing the PDZK1IP1 gene represents a highly recurrent CRC-associated SE
- Higher PDZK1IP1 expression in tumors than cell lines suggests culture-mediated PDZK1IP1 inactivation
- Lower PDZK1IP1 expression in cell lines than normal tissue suggests TME-induced PDZK1IP1 expression
- Cell line growth as subcutaneous xenografts in mice prompts increased H3K27ac levels at the PDZK1IP1 locus – thereby creating the SE – and increasing PDZK1IP1 gene expression
- CRISPR dCas9-KRAB mediated chromatin repression at open chromatin regions within the PDZK1IP1 SE in cell lines inhibits PDZK1IP1 expression in subsequent xenografts
- Open chromatin regions of the PDZK1IP1 SE possess multiple inflammatory transcription factor motifs
- PDZK1IP1 expression correlates with inflammatory signaling; meanwhile, inflammatory cytokines induce PDZK1IP1 expression in cell lines to xenograft-like levels and induce the appearance of the PDZK1IP1 SE
- A comparison between xenografts and cytokine-stimulated cell lines shows a positive correlation between H3K27ac at enhancers
- These findings implicate cytokines and the TME as contributors to CRC-associated enhancer dysregulation
- PDZK1IP1 loss- and gain-of-function in cell lines affects proliferation modestly; however, PDZK1IP1 gain in xenografts leads to significantly increased cell proliferation levels (and vice-versa)
- A role for PDZK1IP1 in regulating reductive ability may have functional relevance to CRC tumor growth
Overall, a microclimate composed of inflammatory signaling with the TME appears to prompt the deposition of H3K27ac at the PDZK1IP1 gene to shape the SE landscape of cancer cells, which then acts to ramp up PDZK1IP1 expression and drive tumorigenesis.
Understand how microenvironmental conditions impact the epigenetic SE landscape at Nature Communications, October 2022.