The inflammatory cytokine IL-6 induces FRA1 deacetylation promoting colorectal cancer stem-like properties

Abstract

Colorectal cancer (CRC) has long been known for its tight association with chronic inflammation, thought to play a key role in tumor onset and malignant progression through the modulation of cancer stemness. However, the underlying molecular and cellular mechanisms are still largely elusive. Here we show that the IL-6/STAT3 inflammatory signaling axis induces the deacetylation of FRA1 at the Lys-116 residue located within its DNA-binding domain. The HDAC6 deacetylase underlies this key modification leading to the increase of FRA1 transcriptional activity, the subsequent transactivation of NANOG expression, and the acquisition of stem-like cellular features. As validated in a large (n = 123) CRC cohort, IL-6 secretion was invariably accompanied by increased FRA1 deacetylation at K116 and an overall increase in its protein levels, coincident with malignant progression and poor prognosis. Of note, combined treatment with the conventional cytotoxic drug 5-FU together with Tubastatin A, a HDAC6-specific inhibitor, resulted in a significant in vivo synergistic inhibitory effect on tumor growth through suppression of CRC stemness. Our results reveal a novel transcriptional and posttranslational regulatory cross-talk between inflammation and stemness signaling pathways that underlie self-renewal and maintenance of CRC stem cells and promote their malignant behavior. Combinatorial treatment aimed at the core regulatory mechanisms downstream of IL-6 may offer a novel promising approach for CRC treatment.

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

“…Interestingly, interference with those pathways by aspirin increased chemosensitivity and decreased self-renewal in breast cancer cells ( 531 ). In colorectal cancer cells the inflammatory cytokine IL-6 mediates deacetylation, which subsequently activates NANOG transcription and accumulation of stemness phenotypes, correlating with malignant progression and poor prognosis ( 543 ).…”

The Prognostic Significance of Global Histones Deacetylation in Colorectal Cancer Patients Treated with Fluoropyrimdine Therapy

“…Aberrant genetic and epigenetic pro iles in numerous types of solid (prostate, breast, colorectal, lung) and haematological malignancies were found to be proportional with the level of their acetylated his-tones (Herceg and Hainaut, 2007). Histone deacetylation induced by the IL-6/STAT3 in lammatory signalling axis was shown to have a role in the transactivation of stemness factors in CRC (Wang et al, 2019). Also, it was found that the initiation, invasion and metastasis of gastrointestinal tumours were correlated with the global content of acetylated histones Chen and Fang (2015).…”

COVID-19–Induced Modifications in the Tumor Microenvironment: Do They Affect Cancer Reawakening and Metastatic Relapse?

“…IL-6 stimulates cancer growth, metastasis and immune evasion in several tumor types (36)(37)(38)(39)(40)(41)(42). Additionally, direct effects of IL-6 on cancer cells include an ability to promote stem cell characteristics (42)(43)(44)(45)(46), induction of mesenchymal traits (39) and resistance to therapies (47). IL-6 orchestrates the interactions between cancer cells and the TME by preparing the soil for cancer homing at target organs (36,48) and has been also shown to stimulate immune evasion by inducing the stabilization of programmed death-ligand 1 (PD-L1) (38).…”