The SLC34A2-ROS-HIF-1-induced up-regulation of EZH2 expression promotes proliferation and chemo-resistance to apoptosis in colorectal cancer

Abstract

Growing evidence has uncovered that plays an evident role in the progression in several types of tumors. However, the biological function and underlying molecular mechanisms of remain largely unknown. Here, we indicated that SLC34A2 expression was markedly increased in SW480 and HT29 cell line cells compared with that in normal colorectal epithelial cell line cells. Array analysis displayed that the expression of EZH2 (enhancer of zeste 2) decreased considerably when was knocked-down. We demonstrated that SLC34A2 induced EZH2 expression and activated its promoter activity. Serial 5' deletion and site-directed mutagenesis revealed that the induction of EZH2 expression by SLC34A2 was dependent upon the hypoxia-inducible factor 1 (HIF1)-2 binding site directly within EZH2 promoter. Moreover, HIF-1 activation was proved essential for SLC34A2-induced EZH2 expression. Reactive oxygen species (ROS) generation contributed to the stabilization of HIF-1α by leading to the binding of HIF-1α to the EZH2 promoter, which resulted in increased EZH2 expression. Additionally, we showed that the inhibition of both HIF-1α expression and ROS generation by YC-1 or BHA, respectively, decreased SLC34A2-induced EZH2 overexpression. Significantly, SLC34A2-induced EZH2 overexpression promoted the proliferation and chemo-resistance to apoptosis in colorectal cancer cells in vitro and in vivo. Altogether, we conclude that the SLC34A2-ROS-HIF-1-induced overexpression of EZH2 promotes colorectal cancer cells proliferation and chemo-resistance to apoptosis. SLC34A2-ROS-HIF-1-EZH2 signaling pathway might serve as a novel therapeutic target against colorectal cancer.

Identification of dysregulated miRNAs‐genes network in ovarian cancer: An integrative approach to uncover the molecular interactions and oncomechanisms

“…Two down‐regulated miRNAs named miR‐660‐3p and hsa‐miR‐4510 show the most interactions with DEGs. Both of them in our study could target some studied oncogenes in other studies including ADAM28, 25 HMGA1 26 and SLC34A2 27 …”

“…Both of them in our study could target some studied oncogenes in other studies including ADAM28, 25 HMGA1 26 and SLC34A2. 27 According to Shyian et al report, the relationship between expression of SLC34A2 and differentiation level of OV tumor cells was confirmed. So, it can be used as a possible marker in determination of cell differentiation.…”

Uncovering the prognostic gene signatures for the improvement of risk stratification in cancers by using deep learning algorithm coupled with wavelet transform

“…It had been found that the expression level of LATS1 had decreased in serous ovarian cancer patients but this gene highly expressed in normal ovarian tissue [52,53]. SLC34A2 was proved to have an evident effect in the progression of several types of cancers, such as in ovarian cancer [54,55], breast cancer and non-small cell lung cancer [56,57]. The gene fusion of SLC34A2 and ROS1 played an important role in the progression of nonsmall cell lung cancer [58].…”

EZH2, HIF-1, and Their Inhibitors: An Overview on Pediatric Cancers

“…In fact, increased ROS stabilize the HIF-1α protein inducing EZH2 overexpression. The silencing of SLC34A2 completely prevented EZH2 overexpression, as well as colorectal cell proliferation and chemo-resistance ( 80 ). Another mechanism through which HIF-1α can increase EZH2 expression has been demonstrated in prostate cancer cells.…”