SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation

Abstract

Epigenetic regulators play a critical role in normal and malignant hematopoiesis. Deregulation, including epigenetic deregulation, of the HOXA gene cluster drives transformation of about 50% of acute myeloid leukemia. We recently showed that the Histone 3 Lysine 9 methyltransferase SETDB1 negatively regulates the expression of the pro-leukemic genes Hoxa9 and its cofactor Meis1 through deposition of promoter H3K9 trimethylation in MLL-AF9 leukemia cells. Here, we investigated the biological impact of altered SETDB1 expression and changes in H3K9 methylation on acute myeloid leukemia. We demonstrate that SETDB1 expression is correlated to disease status and overall survival in acute myeloid leukemia patients. We recapitulated these findings in mice, where high expression of SETDB1 delayed MLL-AF9 mediated disease progression by promoting differentiation of leukemia cells. We also explored the biological impact of treating normal and malignant hematopoietic cells with an H3K9 methyltransferase inhibitor, UNC0638. While myeloid leukemia cells demonstrate cytotoxicity to UNC0638 treatment, normal bone marrow cells exhibit an expansion of cKit+ hematopoietic stem and progenitor cells. Consistent with these data, we show that bone marrow treated with UNC0638 is more amenable to transformation by MLL-AF9. Next generation sequencing of leukemia cells shows that high expression of SETDB1 induces repressive changes to the promoter epigenome and downregulation of genes linked with acute myeloid leukemia, including Dock1 and the MLL-AF9 target genes Hoxa9, Six1, and others. These data reveal novel targets of SETDB1 in leukemia that point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing acute myeloid leukemia.

The circRNA DENND4C/miR-145-5p/HOXA9 Pathway Regulates Tumor Growth and Bone Metastasis in Breast Cancer

“…Among the candidates, HOXA9 was veri ed as a downstream target of miR145-5p by luciferase reporter assays. Many studies reported that HOXA9 is involved in the cell proliferation (40)(41)(42)(43). A previous study demonstrated that HOXA9 regulates myeloid cells and further validated that miR-708 can directly target Meis1, which strongly impedes HOXA9-mediated transformation and homing capacity as well as the induction of myeloid differentiation.…”

SETDB1 promotes glioblastoma growth via CSF-1 - dependent macrophage recruitment by activating the AKT/mTOR signaling pathway

“…These ndings reveal opportunities for research on the role of SETDB1 in disease progression. SETDB1 functions as a histone methyltransferase to cause histone H3K9 trimethylation, which is involved in the formation of heterochromatin [38]. These H3K9 and H3K27 sites are connected to transcriptional regulation and epigenetics [39].…”

“…This presents an opportunity to target epigenetic modi ers such as SETDB1 to treat malignancies. Research has identi ed the overexpression of SETDB1 in many malignancies, such as glioblastoma, melanoma, prostate cancer, and breast cancer (BRC), which was linked to cancer cell division as well as metastasis [23,26,38]. Previously study have shown that SETDB1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proin ammatory cytokines including interleukin-6 through its methyltransferase activity [40].…”

SETDB1 Promotes the Growth of Glioma via CSF-1-dependent Macrophage Recruitment by Activating the AKT/mTOR Signaling Pathway

“…SETDB1 functions as a histone methyltransferase to cause histone H3K9 trimethylation, which is involved in the formation of heterochromatin [34]. These H3K9 and H3K27 sites are connected to transcriptional regulation and epigenetics [35].…”

“…This presents an opportunity to target epigenetic modi ers such as SETDB1 to treat malignancies. Research has identi ed the overexpression of SETDB1 in many malignancies, such asglioma, melanoma, prostate cancer, glioma, and breast cancer (BRC), which was linked to cancer cell division as well as metastasis [19,22,34]. However, a complete picture is lacking in this area of cancer studies.…”