Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation

Abstract

DNA methyltransferase inhibitor (DNMTi) treatments have been used for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and have shown promising beneficial effects in some other types of cancers. Here, we demonstrate that the transcriptional repressor ZBTB38 is a critical regulator of the cellular response to DNMTi. Treatments with 5-azacytidine, or its derivatives decitabine and zebularine, lead to down-regulation of ZBTB38 protein expression in cancer cells, in parallel with cellular damage. The depletion of ZBTB38 by RNA interference enhances the toxicity of DNMTi in cell lines from leukemia and from various solid tumor types. Further we observed that inactivation of ZBTB38 causes the up-regulation of CDKN1C mRNA, a previously described indirect target of DNMTi. We show that CDKN1C is a key actor of DNMTi toxicity in cells lacking ZBTB38. Finally, in patients with MDS a high level of CDKN1C mRNA expression before treatment correlates with a better clinical response to a drug regimen combining 5-azacytidine and histone deacetylase inhibitors. Collectively, our results suggest that the ZBTB38 protein is a target of DNMTi and that its depletion potentiates the toxicity of DNMT inhibitors in cancer cells, providing new opportunities to enhance the response to DNMT inhibitor therapies in patients with MDS and other cancers.

Characterization of hepatitis B virus infection and viral DNA integration in non‐Hodgkin lymphoma

“…Regarding the oncogenic function of these genes, only HDAC4 had been reported before to be involved in lymphoma and leukemia 31,32 . Our results thus provide novel candidate genes for research of their function in NHL, particularly those genes like ANKS1B , 33‐35 ZBTB38 36‐39 and CCDC91 40 that have been reported to play an oncogenic role in other cancers. Given their increased expressions in NHL, the pathological functions of these three genes in NHL are worth further investigation.…”

DNA Methylation Readers and Cancer: Mechanistic and Therapeutic Applications

“…In bladder cancer cells, ZBTB38 increased cell migration, invasion, and metastasis via regulating genes belonging to the Wnt/β-catenin signaling pathway but decreased bladder cancer cell proliferation (65). Depletion of ZBTB38 increases the cytotoxic ability of DNMT inhibitors in different solid and hematological cancer cell lines by increasing the expression of Cyclin-Dependent Kinase Inhibitor 1C ( CDKN1C ) which opens up a new avenue to increase the therapeutic response to DNMT inhibitors (189).…”

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

“…Standard western blotting was conducted as previously described [80]. Cells were lysed and sonicated in Pierce RIPA SDS buffer (ThermoFisher Scientific, 89901) with protease inhibitor (phenylmethylsulfonyl fluoride and cOmplete TM protease inhibitor cocktail tablets) for 1 hour on ice with 1 µL of benzonase (Sigma-Aldrich, E1014) per ten million cells.…”