Researchers found that through inheritable changes of gene expression, chronic exposure to IL-1β can promote lung cancer metastasis, without altering DNA sequence.
Chemical inhibition of DNA methylation not only restored E-cadherin expression in epithelial-to-mesenchymal (EMT) memory, but it also primed cells for chemotherapy-induced apoptosis, according to a study published in Scientific Reports.1
Researchers indicated that inhibition of this pathway may contribute to both the prevention and treatment of non-small cell lung cancer (NSCLC).
“Our studies amplify mechanistic insights implicating IL-1Î²-regulated chronic inflammation as a central component in carcinogenesis and metastasis,” the authors wrote.
The heightened incidence of cancer and resulting mortality in patients with chronic inflammatory conditions highlights the gravity of chronic inflammation in tumor initiation, progression, and metastasis. Through inheritable changes of gene expression, researchers discovered that chronic exposure to IL-1Î² can promote lung cancer metastasis, without altering DNA sequence.2 Due to these gene alterations, cancer cells can memorize this phenotype to successfully reach distant organs and later colonize.
In this study, the researchers looked at the role of IL-1Î² in lung cancer metastasis by examining in vitro models of lung cancer to potentially provide insight into the cells’ behaviors. This revealed that the EMT and EMT-associated phenotypes, including enhanced cell invasion, PD-L1 upregulation, and chemoresistance, were sustained in the absence of continuous IL-1Î² exposure. Researchers referred to this occurrence as EMT memory.
Employing a doxycycline-controlled slug expression system, researchers discovered that high expression of the transcription factor SLUG was crucial for the establishment of EMT memory. High SLUG expression in the rumors of lung cancer patients was associated with poor survival. Additionally, it was found that chemical or genetic inhibition of SLUG upregulation was able to prevent EMT following the acute IL-1Î² exposure but did not reverse EMT memory.
Chromatin immunoprecipitation and methylation-specific PCR further displayed a SLUG-mediated temporal regulation of epigenetic modifications, including accumulation of H3K27, H3K9, and DNA methylation, in the CDHI (E-cadherin) promoter following the chronic IL-1Î² exposure.
“This study reveals distinct molecular events modulating acute and chronic inflammation, thus enhancing our understanding of the temporal-spatial regulation of EMT during metastasis,” the authors wrote.
The researchers noted that future studies tracking these epigenetic alterations at single cell resolution in this inflammation induced EMT model will address the possibility that these previously formed epigenetic modifications are diluted upon cell divisions, and also further dissect the composition of the epigenetic machinery in maintaining gene silencing.
According to the researchers, EMT plays a pivotal role in cancer metastasis, as it endows metastatic cells with migratory and invasive properties, apoptosis resistance, and immune invasion. Though researchers had already identified that the EMT program can be activated in response to pathologic signals, the mechanisms by which metastatic cells maintain the mesenchymal properties following detachment from the primary tumor and subsequently regain the epithelial status to form macro-metastases was unknown.
1. Li R, Ong S, Tran LM, et al. Chronic IL-1Î²-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer. Scientific Reports. doi:10.1038/s41598-019-57285-y.
2. UCLA researchers find chronic inflammation contributes to cancer metastasis [news release]. Los Angeles, California. Published January 29, 2020. cancer.ucla.edu/Home/Components/News/News/1438/1631. Accessed January 31, 2020.