Suppression of RAD21 gene expression decreases cell growth and enhances cytotoxicity of etoposide and bleomycin in human breast cancer cells

Abstract

A genome-wide case-control association study done in our laboratory has identified a single nucleotide polymorphism located in RAD21 as being significantly associated with breast cancer susceptibility. RAD21 is believed to function in sister chromatid alignment as part of the cohesin complex and also in double-strand break (DSB) repair. Following our initial finding, expression studies revealed a 1.25- to 2.5-fold increased expression of this gene in several human breast cancer cell lines as compared with normal breast tissue. To determine whether suppression of RAD21 expression influences cellular proliferation, RNA interference technology was used in breast cancer cell lines MCF-7 and T-47D. Proliferation of cells treated with RAD21-specific small inhibitory RNA (siRNA) was significantly reduced as compared with mock-transfected cells and cells transfected with a control siRNA (Lamin A/C). This inhibition of proliferation correlated with a significant reduction in the expression of RAD21 mRNA and with an increased level of apoptosis. Moreover, MCF-7 cell sensitivity to two DNA-damaging chemotherapeutic agents, etoposide and bleomycin, was increased after inhibition of RAD21 expression with a dose reduction factor 50 (DRF50) of 1.42 and 3.71, respectively. At the highest concentrations of etoposide and bleomycin administered, cells transfected with a single siRNA duplex targeted against RAD21 showed 57% and 60% survival as compared with control cells, respectively. Based on these findings, we conclude that RAD21 is a novel target for developing cancer therapeutics that can potentially enhance the antitumor activity of chemotherapeutic agents acting via induction of DNA damage.

The effect of aberrant expression and genetic polymorphisms of Rad21 on cervical cancer biology

“…The protein interaction network of Rad21 and its coexpressed genes was mapped (Figure ). KEGG pathway analysis (Figure ) showed that Rad21 was associated with the cell cycle and RNA transport . CRM1/chromosome region stabilizing protein (XPO1, export protein 1) is involved in RNA transport under the action of RNA polymerase, whose function is highly related to Rad21 protein expression (Figures and ).…”

Identification of Aging-Related Genes Associated With Clinical and Prognostic Features of Hepatocellular Carcinoma

“…In the current study, all seven AGs were related to the cell cycle. Classical cell cycle–specific agents such as etoposide, irinotecan, and bleomycin have been used prevalently in various cancers (Atienza et al, 2005 ), and many novel drugs such as palbociclib and CFI-402257 are also related to the cell cycle (Thu et al, 2018 ). As a member of CDKs, CDK1 plays a crucial role in the cell cycle process (Xiao et al, 2016 ).…”

Histone deacetylases facilitate the accurate repair of broken forks

“…Indeed, artificially diminishing the expression of the RAD21 gene (RADiation sensitive 21), which encodes for one of the cohesin components, was reported to enhance the cytotoxicity of the DNA damaging agents etoposide and bleomycin in cancer cells. 10 A similar effect would be expected by HDAC inhibitors that affect SCR through cohesion impairment. Moreover, it is worthy of note that the genetic instability caused by HDAC inhibition might also contribute to the development of new tumoral processes or chemoresistance by promoting the acquisition of extra mutations.…”