Stromal signal promotes Chromatin Remodeling and BET inhibitor Resistance in Cancer cells
BRD4 has a pro-tumorigenic role but non-cell-autonomous mechanisms of BRD4 activation need to be elucidated. Here the authors unravel a mechanism by which CAFs activate BRD4 and induce resistance to BET inhibitors in cancer cells through IL6/IL8 signaling.
BET (Bromodomain and extraterrestrial) family proteins, particularly BRD4, which are important transcriptional and epigenetic regulators, play critical roles during cancer development, thus elicited a great level of interest in developing BET inhibitors (BETi) for cancer treatment. Currently, multiple BETi inhibitors have entered clinical trials, including colorectal cancer (CRC). However, BET inhibitor resistance often emerges. Current studies have been focusing on the cancer cell autonomous mechanism of resistance to BETi. Recently, several BET inhibitors such as dBET1, MZ1, which employed proteolysis-targeting chimeras (PROTACs) technology to degrade BRD4, have been developed to conquer BET resistance caused by BRD4 stabilization. However, resistance to BET-PROTACs has also been reported. Moreover, BETi in solid tumors is not as effective as in hematological malignance. These indicate new and extrinsic resistance mechanism associated with tumor microenvironment (TME) in solid tumors.
Pro-inflammatory factors secreted from the tumor microenvironment are important hallmarks of cancer, which contributes to almost every aspect of tumorigenesis, metastasis and therapeutic resistance. Although pro-inflammatory factors are well known to promote tumorigenesis via activating vital signaling pathways, it is less investigated whether and how they crosstalk with cancer epigenetic landscape including chromatin modulation to shape the biological behaviors of the tumor.
Recently, a research article in Nature Communications entitled “Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer” reported a previously unrecognized mechanism by which the stroma cells in tumor microenvironment promote chromatin reprogramming and BETi resistance through paracrine secretion of cytokines.
The study uncovered that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. Intriguingly, while phosphorylation at Y97/98 appears to reduce BRD4 inhibitor (e.g., JQ1) and degrader (dBET1) binding to the BRD4, pY97/98 in fact promotes BRD4 binding to oncogenic enhancers/super-enhancers through increased association with phosphor-STAT3 and chromatin histones. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. This finding provides a promising combination treatment regimen using inhibitors targeting IL6 receptor (tocilizumab), IL8 receptor (reparixin), JAK2 (pacritinib), or perhaps UCHL3, in combination with a BRD4 inhibitor (e.g., JQ1), to overcome therapeutic CRC resistance via blocking the IL6/8-JAK2 paracrine signaling axis that is more effective than single-agent treatment.The study also highlights the important interaction between inflammatory signaling in the tumor microenvironment and chromatin regulatory mechanisms in cancer cells, providing new insights into the tumor progression and drug resistance of CRC.