Zinc-Finger Protein 545 Inhibits Cell Proliferation as a Tumor Suppressor through Inducing Apoptosis and is Disrupted by Promoter Methylation in Breast Cancer

Abstract

Krüppel-associated box-containing zinc finger proteins (KRAP-ZFPs) are well recognized as key regulators of transcription, which play a crucial role in the regulation of cell proliferation, differentiation, apoptosis and tumorigenesis. We previously identified a KRAP-ZFP protein ZNF545 acting as a tumor suppressor involved in tumor pathogenesis. However, its expression and biological function in breast cancer remain elusive. In this study, we found that ZNF545 was frequently downregulated in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and human epidermal growth factor receptor 2-negative (HER2−) breast tumor tissues compared with paired adjacent non-tumor tissues. We further examined its expression and methylation in breast cancer cell lines by semi-quantitative RT-PCR and methylation-specific PCR. We found that ZNF545 was silenced by promoter methylation in MCF7 cell line, and its expression could be restored by demethylation, concomitant with increased unmethylated alleles. ZNF545 methylation was detected in 29% of breast tumor tissues, but not in normal breast tissues, suggesting tumor-specific methylation of ZNF545 in breast cancer. Ectopic expression of ZNF545 in MCF7 cells inhibited cell proliferation through inducing cell cycle G0/G1 arrest and apoptosis, thus as a tumor suppressor. Moreover, ZNF545 upregulated mRNA and protein levels of c-Jun/AP1, BAX, p53 and Caspase 3. Taken together, these results demonstrate that ZNF545 inhibits breast tumor cell proliferation through inducing apoptosis and is disrupted by promoter methylation in breast cancer.

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

“…Notable genes include: ZFP82 , which is epigenetically silenced and suspected to function as a tumor suppressor (Xiao et al, 2014) (Yu et al, 2015) (Fan et al, 2016); PARP6 hypermethylation (Honda et al, 2016) (Qi et al, 2016); DNAJC15, which is hypermethylated in a number of tumor types (Ehrlich et al, 2002; Lindsey et al, 2006), and whose inactivation has been associated with chemotherapeutic drug resistance in breast (Fernandez-Cabezudo et al, 2016) and ovarian cancers (Rein et al, 2011). We also identified genes that were epigenetically silenced at low prevalence through manual examination of the genes known to be important in cancer, including BRCA1 and MGMT (each silenced in one case).…”

Protocadherin 17 functions as a tumor suppressor suppressing Wnt/β-catenin signaling and cell metastasis and is frequently methylated in breast cancer

“…The expression of many TSGs, such as BRCA1 , ERa and RASSF1A are downregulated in breast cancer, by promoter methylation [2–5]. Our group also identified some TSGs methylation in breast cancer, including DACT1 , ZNF545 , PLCD1 , UCHL1 , DKK3 , which contributes to tumor malignant progression [6–10]. Promoter methylation is the primary mechanism for transcriptional repression of TSGs, thus could serve as a biomarker for early detection of breast cancer [2, 11–14].…”

Low BIK outside-inside-out interactive inflammation immune-induced transcription-dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384

“…Apoptosis-enhancing nuclease (AEN) is required for p53-dependent apoptosis; endo-exonuclease plays a role in apoptosis of HL-60 cells (SFN_2 and ANE are related to exonuclease) [35,36]. Promyelocytic leukemia zinc finger protein (PLZF) promotes glucocorticoidinduced apoptosis in leukemic cell line NALM6; zinc finger protein 545 (ZNF545) induces apoptosis in breast cancer (ZNF384 belongs to zinc finger protein family) [37,38].…”

“…Bcl-2 interacts with sequestosome 1 to upregulate autophagy in vitro (SQSTM1 is related to sequestosome protein) [40]. The expressions of Bcl-2 are promoted by zinc finger 139 (ZNF139) involved in multi-drug resistance of gastric cancer cells; mRNA and protein levels of BCL2-associated X protein (BAX) are upregulated by zinc finger 545 (ZNF545) in breast cancer [38,41].…”