Oncogene SETDB1’s dual role in endometrial cancer: driving tumor progression and immune escape

We all know a driver is necessary for a car to run. SETDB1 (ESET/KMT1E) is one such driver gene in cancer promoting the growth in endometrial cancer (EC) as well as many other cancers. We found that removing SETDB1 in EC significantly slows down tumor growth and prolongs tumor-bearing mice survival by 100 days. As one mouse day equals 40 human days, these 100 mouse days are equivalent to 10 years of human life. Yet, the roles of SETDB1 in driving EC progression is not well-studied. We showed that depletion of SETDB1 decreased EC cells division as well as the cell division fidelity. Further, our data illustrates that SETDB1 promotes important oncogenes and represses tumor suppressors. The oncogenes have implication in promoting tumor growth while tumor suppressor genes have an inverse role in cancer. While SETDB1 affected cancer cells intrinsically, it also showed to suppress the immune system to promote the survival of the tumor. In our study, we observed that removing SETDB1 promoted macrophages entering the tumor environment. When macrophages are stimulated to become anti-tumor, they promote greater cell death in SETDB1 depleted cancer cells. We found that SETDB1 suppresses CCL5 production in cancer cells, an important factor responsible for recruitment of macrophages toward the tumor. Our analysis of publicly available tumor profiles suggests that tumors with higher level of SETDB1 correlated with higher level of tumor promoting genes and reduced immune response genes. Our novel findings suggest SETDB1 is a promising anticancer target for EC patients.