The ZNF750–RAC1 axis as potential prognostic factor for breast cancer

Abstract

The human zinc finger (C2H2-type) protein ZNF750 is a transcription factor regulated by p63 that plays a critical role in epithelial tissues homoeostasis, as well as being involved in the pathogenesis of cancer. Indeed, missense mutations, truncation and genomic deletion have been found in oesophageal squamous cell carcinoma. In keeping, we showed that ZNF750 negatively regulates cell migration and invasion in breast cancer cells; in particular, ZNF750 binds and recruits KDM1A and HDAC1 on the LAMB3 and CTNNAL1 promoters. This interaction, in turn, represses the transcription of LAMB3 and CTNNAL1 genes, which are involved in cell migration and invasion. Given that ZNF750 is emerging as a crucial transcription factor that acts as tumour suppressor gene, here, we show that ZNF750 represses the expression of the small GTPase, Ras-related C3 botulinum toxin substrate 1 (RAC1) in breast cancer cell lines, by directly binding its promoter region. In keeping with ZNF750 controlling RAC1 expression, we found an inverse correlation between ZNF750 and RAC1 in human breast cancer datasets. More importantly, we found a significant upregulation of RAC1 in human breast cancer datasets and we identified a direct correlation between RAC1 expression and the survival rate of breast cancer patient. Overall, our findings provide a novel molecular mechanism by which ZNF750 acts as tumour suppressor gene. Hence, we report a potential clinical relevance of ZNF750/RAC1 axis in breast cancer.

Resveratrol suppresses malignant progression of oral squamous cell carcinoma cells by inducing the ZNF750/RAC1 signaling pathway

“…Our observations have reported that resveratrol inhibited cell proliferation and induced apoptosis in CAL-27 cells by suppressing the expression of RAC1. In addition, ZNF750 overexpression also decreased the RAC1 expression, whereas its underexpression induced RAC1 level, which is consistent with previous investigation [16]. In our study, RAC1 agonist partially reversed the inhibitory effects of resveratrol on OSCC cell growth.…”

“…When activated, RAC1 is involved in the cell migration, through a cytoskeleton rearrangement, and in cell survival [13][14][15]. Furthermore, ZNF750 represses the expression of RAC1 in breast cancer cell lines, by directly binding its promoter region [16].…”

Long non-coding RNAs affecting cell metabolism in cancer

“…However, we still need to uncover specific biomarkers that can assist in diagnosis, prognosis and proper treatment for each patient [31,32]. We have recently shown the involvement of the p53 family [33][34][35][36][37][38] and in particular of p63 via the regulation of Sonic Hedgehog in the control of breast cancer proliferation [39][40][41][42][43][44], its transcriptional target ZNF750 [45,46], as well as p73 [47]. These molecular mechanisms also showed the involvement of long noncoding RNA uc.63 [48].…”

ZNF750: A Novel Prognostic Biomarker in Metastatic Prostate Cancer

“…A low expression level of ZNF750 correlates with a higher incidence of undifferentiated histology and is associated with malignant progression and poor prognosis in SCC patients. We have recently reported that ZNF750 inhibits the migratory and invasive properties of breast cancer cells by recruiting the epigenetic platform KDM1A/HDAC1 to the genetic loci of LAMB3 and CTNNAL1, ultimately repressing their expression [ 21 , 22 ].…”