Inflammatory Cytokine IL-6 Induces FRA1 Deacetvlation Promoting Colorectal Cancer Stemness And Aggressiveness

Colorectal cancer(CRC)has long been known for its tight association with chronic inflammation,thought to play a key role in tumor onset and aggressiveness through the modulation of cancer sternness.However,the underlying molecular and cellular mechanisms are still largely elusive.Cancer Stem Cells(CSCs),are a small subpopulation of cancer cells which are capable of unlimited proliferation,self-renewal,and the increased probability of tumor formation.Traditional methods of treating cancer focus on most cancer cells without affecting drug-resistant cancer stem cells that can cause clinical relapse.New treatments that specifically target cancer stem cells are important for eradicating tumor recurrence and tolerance.Inflammation can provide tumors with growth factors,cytokines and other tumor microenvironments,and play a pivotal role in maintaining tumor stem cell self-renewal.Therefore,studying the specific regulation mechanism of inflammatory microenvironment on colorectal cancer stem cells has important clinical significance for targeted therapy of colorectal cancer stem cells.Therefore,studying the specific regulation mechanism of inflammatory environment on CRC stem cells has important clinical significance for the targeted therapy of CRC stem cells.Here,we did in vitro and in vivo expriments and showed that the predominant inflammatory signaling axis IL-6/STAT3 induced FRA1 deacetylation at Lys(k)-116 in DNA-binding domain by the deacetylase HDAC6 to increase its transcriptional activity,which then directly transactivated NANOG expression thereby driving sternness and aggressiveness of CRC.As validated in a large(n=123)cohort of CRC cases,IL-6 secretion was invariably accompanied by the increased FRA1 protein level and deacetylation at K116 in the cancer cell nucleaus,coincident with CRC patients aggressiveness and poor prognosis.Importantly,combined treatment of the bulky cancer killer 5-FU with the specific HDAC6 inhibitor Tubastatin A resulted in a highly potent synergistic inhibitory effect on in vitro proliferation and in vivo tumor growth through suppression of CRC stemness.Thus,our results reveal a novel mechanism of enhanced CRC malignancy by tumor microenvironmental inflammatory cytokines through regulating post-translational modification of key transcriptional factors to hijack cell sternness pathways.Combinatorial treatment aimed at the core regulatory mechanisms may offer a novel promising approach for CRC elimination.