MED28 increases the colony‑forming ability of breast cancer cells by stabilizing the ZNF224 protein upon DNA damage

Abstract

Abstract. The regulation of gene expression by transcription factors serves a critical function in cell proliferation. Zinc-finger protein 224 (ZNF224), a Krüppel-associated-box-containing zinc finger protein, is known to serve a crucial function in integrating the transcriptional co-factors that activate transcriptional regulation pathways in the cell. A previous study demonstrated that ZNF224 enhances cell proliferation by downregulating the expression of p21 and p53. The present study identified mediator complex subunit 28 (MED28) as a potential binding partner for ZNF224; this was confirmed by co-immunoprecipitation and a surface plasmon resonance assay. Additionally, the KRAB domain at the N-terminal of ZNF224 interacts with the MED domain of MED28. Bimolecular fluorescence complementation analysis revealed that ZNF224 associates with MED28 in the nucleus. In addition, ZNF224 was rapidly degraded upon treatment with the DNA-damaging agent camptothecin (CPT). Transient overexpression of MED28 inhibited the CPT-mediated degradation of ZNF224, resulting in increased colony formation by MCF-7 cells. The molecular mechanisms that underlie the biological outcomes of MED28 expression have not yet been fully elucidated. The present study provides molecular evidence for the function of ZNF224 and MED28 in the DNA-damage response.

MED28 Over-Expression Shortens the Cell Cycle and Induces Genomic Instability

“…Recent studies indicate that the overexpression of MED28 induces cancer cell proliferation and increases the colony-forming ability of cancer cells upon DNA damage [11,13]. In this study, we first identified four transcription factors, namely E2F-1, NRF-1, ETS-1, and C/EBPβ, which increase the expression level of MED28 .…”

“…MED28 is highly expressed in breast, colon, and prostate cancers, and MED28 induces cancer cell proliferation via the mitogen-activated protein kinase kinase-1 (MAP2K1) signaling pathway [10,11,12]. Recently, we reported that the interplay between MED28 and ZNF224, a Krüppel-associated-box-containing zinc finger protein transcriptional cofactor, was associated with cancer cell proliferation upon initiation of the DNA damage response [13]. A study in knockout mice has shown that the genetic deletion of MED28 results in peri-implantation embryonic lethality by reducing the expression of OCT4 and NANOG, which are pluripotency transcription factors [14].…”

“…Although the molecular mechanisms underlying MED28-mediated oncogenesis are unknown, previous studies have suggested that MED28 can increase cancer cell proliferation, and phenotypes that are related to the dysregulation of MED28 have been demonstrated in breast cancer cells [11,13,19,20]. In this study, we aimed to identify and characterize the transcription factors that increase MED28 expression and investigated the involvement of MED28 in cell cycle regulation.…”

Low Levels of TRIM28-Interacting KRAB-ZNF Genes Associate with Cancer Stemness and Predict Poor Prognosis of Kidney Renal Clear Cell Carcinoma Patients

“…Among the tested KRAB-ZNFs, numerous studies demonstrate significant engagement of ZNF224 in the regulation of cancer development and progression, especially in melanoma [ 37 ], breast cancer [ 38 , 39 ], and Wilms tumor [ 40 ]. However, the data for clear cell kidney carcinoma are still missing.…”

Comprehensive Transcriptome Analysis Reveals Insights into Phylogeny and Positively Selected Genes of Sillago Species

“…To reveal the molecular mechanism underlying the ecological adaptation of Sillago species, we estimated the dN/dS to identify the PSGs of Sillago species. A total of 44 orthologous genes were identified to be positively selected and might be involved in many biological processes, including the stress response (LTV1 [44], SMO [45], PSA [46,47], ABCB7 [48], UBIAD1 [49], COPA [50], MED27 [51,52], MED28 [51,52], SF3A1 [53], SF3B5 [53], TFIP11 [54], NUDT6 [55], POLλ [56], and DEPDC5 [57]), energy metabolism (APF [58] and IMMT [59]), carbohydrate metabolism (SUCLG1 [60]), amino acid metabolism (GCN4 [61] and CPD [62]), lipid metabolism (HUWE1 [63] and FABZ [64]), visual sense (AP4B1 [65] and PRPF8 [66]), growth and differentiation (ABTB1 [67], UBE4A [68], DOHH [69], and GAB1 [70]), embryogenesis (SBDS [71], TAF5L [72], and SEC8 [73]), and others.…”