Abstract
Renal Cell Carcinoma (RCC) in humans is positively influenced by oxidative stress status in kidneys. We recently reported that adaptive response to low level of chronic oxidative stress induces malignant transformation of immortalized human renal tubular epithelial cells. Epigenetic alterations in human RCC are well documented, but its role in oxidative stress-induced malignant transformation of kidney cells is not known. Therefore, the objective of this study was to evaluate the potential role of epigenetic changes in chronic oxidative stress-induced malignant transformation of HK-2, human renal tubular epithelial cells. The results revealed aberrant expression of epigenetic regulatory genes involved in DNA methylation (DNMT1, DNMT3a and MBD4) and histone modifications (HDAC1, HMT1 and HAT1) in HK-2 cells malignantly transformed by chronic oxidative stress. Additionally, both in vitro soft agar assay and in vivo nude mice study showing decreased tumorigenic potential of malignantly transformed HK-2 cells following treatment with DNA de-methylating agent 5-aza 2’ dC further confirmed the crucial role of DNA hypermethyaltion in oxidative stress-induced malignant transformation. Changes observed in global histone H3 acetylation (H3K9, H3K18, H3K27 and H3K14) and decrease in phospho-H2AX (Ser139) also suggest potential role of histone modifications in increased survival and malignant transformation of HK-2 cells by oxidative stress. In summary, the results of this study suggest that epigenetic reprogramming induced by low levels of oxidative stress act as driver for malignant transformation of kidney epithelial cells. Findings of this study are highly relevant in potential clinical application of epigenetic-based therapeutics for treatments of kidney cancers.
Highlights
Renal cell carcinoma (RCC) originates from renal tubular epithelial cells and is the most common cancer of the genitourinary system, next to prostate and bladder cancer [1]
We recently reported that adaptive response to low level of chronic oxidative stress induces malignant transformation of immortalized human renal tubular epithelial cells potentially through acquisition of epithelial to mesenchymal transition (EMT) and stem cell characteristics [7]
HK-2 human kidney epithelial cells malignantly transformed by chronic exposure to oxidative stress were used to evaluate the role of epigenetic changes in oxidative stress-induced carcinogenesis
Summary
Renal cell carcinoma (RCC) originates from renal tubular epithelial cells and is the most common cancer of the genitourinary system, next to prostate and bladder cancer [1]. Elevated but low levels of ROS act as key cell signaling molecules and can induce cell proliferation and transformation [4,5,6]. Elevated levels of ROS causing oxidative stress has been implicated in carcinogenesis through transcriptional regulation of genes. Upregulation of genes involved in cell cycle progression from G1 to S phase such as different Cyclins (Cyclin D3, Cyclin B2 and, Cyclin E1) [6], up-regulation of antiapoptotic gene Bcl-2 [12], increased expression of genes involved in cell motility and migration such as MMPs [13] and Snail, a key transcription factor regulating EMT and E-cadherin [14] by oxidative stress are known. The precise mechanism through which the ROS controls the transcriptional regulation of genes is not clear
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