ZNF423: A New Player in Estrogen Receptor-Positive Breast Cancer

Abstract

Preventive therapy can target hormone-responsive breast cancer (BC) by treatment with selective estrogen receptor modulators (SERMs) and reduce the incidence of BC. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) with relevant predictive values, SNPs in the ZNF423 gene were associated with decreased risk of BC during SERM therapy, and SNPs in the Cathepsin O gene with an increased risk. ZNF423, which was not previously associated with BC is a multifunctional transcription factor known to have a role in development, neurogenesis, and adipogenesis and is implicated in other types of cancer. ZNF423 is transcriptionally controlled by the homolog ZNF521, early B cell factor transcription factor, epigenetic silencing of the promoter by CpG island hyper-methylation, and also by ZNF423 itself in an auto-regulatory loop. In BC cells, ZNF423 expression is found to be induced by estrogen, dependent on the binding of the estrogen receptor and calmodulin-like 3 to SNPs in ZNP423 intronic sites in proximity to consensus estrogen response elements. ZNF423 has also been shown to play a mechanistic role by trans-activating the tumor suppressor BRCA1 and thus modulating the DNA damage response. Even though recent extensive trial studies did not classify these SNPs with the highest predictive values, for inclusion in polygenic SNP analysis, the mechanism unveiled in these studies has introduced ZNF423 as a factor important in the control of the estrogen response. Here, we aim at providing an overview of ZNF423 expression and functional role in human malignancies, with a specific focus on its implication in hormone-responsive BC.

DNA Methylome Distinguishes Head and Neck Cancer from Potentially Malignant Oral Lesions and Healthy Oral Mucosa

“…The first fifteen genes that were significantly hypomethylated on different sites across the genome in cancer tissues in comparison to control healthy tissues, named ATXN1 , PPP2R2C , CCR6 , RAB37 , DUSP27 , ZNF521 , SLC6A17 , SPIN1 , CXCR1 , SPTBN1 , NBAS , NRG3 , COL5A1 , CDX1 , and BATF3 are mostly involved in transcriptional and immune regulation. Among this group of genes, aberrantly methylated in other human cancers were CCR6 in oral cancer [ 38 ] and chronic lymphocytic leukemia [ 39 ], RAB37 in lung cancer [ 40 ], ZNF521 in breast cancer [ 41 ], and CDX1 in gastric cancer [ 42 ], esophageal SCC [ 43 ], and in colon cancer [ 44 ]. The genes involved in the immune regulation could belong to the tumor-infiltrating immune cells or tumor-infiltrating lymphocytes, which are often associated with better clinical outcomes.…”

Roles of Zinc Finger Protein 423 in Proliferation and Invasion of Cholangiocarcinoma through Oxidative Stress

“…In addition, ZNF423 could promote adipogenesis via the peroxisome proliferator-activated receptor γ (PPARγ) pathway [6,7]. Besides, this protein has been identified as an important transcriptional modulator in several types of cancer, such as acute lymphoblastic leukemia (ALL) [8], chronic myelogenous leukemia (CML) [9], nasopharyngeal carcinoma (NPC) [10], neuroblastoma (NB) [11], and breast cancer (BC) [12,13]. In ALL, ZNF423 inhibits transcriptional factor of B-cell differentiation (EBF1) leading to B-cell maturation arrest [8].…”

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease

“…ZNF423 is likely involved with centrosomes and DNA damage repair [26]. It is downregulated in human neuroblastoma and glioma [52] [53] and also has a role in breast cancer [54]. Previously, it also has been shown that missense and LoF variants are likely to be pathogenic for abnormality of brain morphology, Joubert syndrome and Nephronophthisis with autosomal dominant or autosomal recessive inheritance (www.omim.org, https://www.ncbi.nlm.nih.gov/clinvar/).…”