Silencing of ZRF1 impedes survival of estrogen receptor positive MCF-7 cells and potentiates the effect of curcumin

Abstract

The role and clinical implication of ZRF1 in breast cancer are poorly understood. So this study is aimed to explore the role of ZRF1 in breast cancer progression. With this context, we first assessed its expression pattern in FFPE primary and metastasis breast tissue samples as well as from publicly available databases. Moreover, we also explored the survival status of patients from the publicly available database and interestingly discover that high expression of ZRF1 decreases the survival of estrogen-positive breast cancer patients more than estrogen-negative status patients. In the perspective of this, we evaluated the role ZRF1 in MCF-7 breast cancer cells and found that it's silencing by knockdown results in decreased cell proliferation as well as cell viability. Results also show that expression of ZRF1 is down regulated in the presence of estrogen-depleted conditions but independent of RAS/MEK as well as AKT axes. Moreover, the decrease in viability of MCF-7 cells was accompanied by induction of apoptosis and DNA damage, well-marked with upregulation of cleaved PARP and downregulation of BCL2 and H2AUbK119 levels. Furthermore, we also explored that knockdown of ZRF1 sensitises the effect of curcumin, observed with decrease in cell viability and dropping of IC50 value from 25 to 15 μM. This investigation thus shed a new light on the role on ZRF1 in breast cancer cells and hence can be exploited to design better therapeutic intervention.

Role for the transcriptional activator ZRF1 in early metastatic events in breast cancer progression and endocrine resistance

“…This observation is in agreement with a previous report describing ZRF1 as a tumor suppressor that regulates the INK4/ARF locus epigenetically and protects genomic integrity during the cell cycle [ 43 , 64 ]. However, we did not observe a similarly strong effect on cell growth in breast cancer cell lines when depleting ZRF1 compared to the dramatic growth phenotypes exhibited after ZRF1 knockdown in other cancer types [ 43 , 65 , 66 ]. Unlike for cell invasion, we noticed differences in cell proliferation and migration properties of shZRF1 cells when cultured in monolayer and in suspension.…”

Neuronal Differentiation-Related Epigenetic Regulator ZRF1 Has Independent Prognostic Value in Neuroblastoma but Is Functionally Dispensable In Vitro

“…Focusing on the role of PRC1 in neuronal differentiation, Aloia et al identified ZRF1 as a transcriptional regulator of neural fates in embryonic stem cells [ 9 ]. Furthermore, ZRF1 expression has been associated with poor outcomes in other tumors, such as breast [ 14 , 31 ] or gastric cancer [ 15 ], thus suggesting an oncogenic role in cancer. Thus, we sought to determine whether ZRF1 plays a functional role in aggressive neuroblastomas.…”

“…Although ZRF1 is not sufficient to provide oncogenic advantages, it could still be necessary to maintain the undifferentiated and highly proliferative state of neuroblastoma cells. Previous reports demonstrated that depletion of ZRF1 resulted in a reduction of cell proliferation and the induction of apoptosis in gastric [ 15 ] or breast cancer models [ 14 ]. Conversely, Kaymak et al also showed that the reduction in cell proliferation mediated by ZRF1 depletion was accompanied by an increase in the migration and invasion properties of breast cancer cells [ 31 ].…”

“…In addition to its physiological role in the maintenance of the pluripotency of neural progenitor cells, ZRF1 has already been functionally implicated in cancer. ZRF1 was shown to be oncogenic in solid tumors such as breast [ 14 ] and gastric [ 15 ] cancers. Furthermore, ZRF1 was shown to be overexpressed in acute myeloid leukemia (AML) acting as a negative regulator of differentiation.…”

Biofilm Impeding AgNPs Target Skin Carcinoma by Inducing Mitochondrial Membrane Depolarization Mediated through ROS Production

“…The DNA bands were observed though the gel documentation system (Bio-Rad). To further validate the DNA damage at the single-cell level, the comet assay was performed following the protocol of Rath et al 17 Briefly, the harvested cells were mixed with low-melting-point agarose, and a layer was made on an agarose-coated glass slide. The glass slides were preincubated in an alkaline lysis solution followed by electrophoresis and PI staining for 15 min.…”