Frequent Inactivation of Cysteine Dioxygenase Type 1 Contributes to Survival of Breast Cancer Cells and Resistance to Anthracyclines

Abstract

Purpose Genome-wide DNA methylation analyses have identified hundreds of candidate DNA-hypermethylated genes in cancer. Comprehensive functional analyses provide an understanding of the biologic significance of this vast amount of DNA methylation data that may allow the determination of key epigenetic events associated with tumorigenesis. Experimental Design To study mechanisms of cysteine dioxygenase type 1 (CDO1) inactivation and its functional significance in breast cancer in a comprehensive manner, we screened for DNA methylation and gene mutations in primary breast cancers and analyzed growth, survival, and reactive oxygen species (ROS) production in breast cancer cells with restored CDO1 function in the context of anthracycline treatment. Results DNA methylation-associated silencing of CDO1 in breast cancer is frequent (60%), cancer specific, and correlates with disease progression and outcome. CDO1 function can alternatively be silenced by repressive chromatin, and we describe protein-damaging missense mutations in 7% of tumors without DNA methylation. Restoration of CDO1 function in breast cancer cells increases levels of ROS and leads to reduced viability and growth, as well as sensitization to anthracycline treatment. Priming with 5-azacytidine of breast cancer cells with epigenetically silenced CDO1 resulted in restored expression and increased sensitivity to anthracyclines. Conclusion We report that silencing of CDO1 is a critical epigenetic event that contributes to the survival of oxidative-stressed breast cancer cells through increased detoxification of ROS and thus leads to the resistance to ROS-generating chemotherapeutics including anthracyclines. Our study shows the importance of CDO1 inactivation in breast cancer and its clinical potential as a biomarker and therapeutic target to overcome resistance to anthracyclines.

Epigenetics Markers of Metastasis and HPV-Induced Tumorigenesis in Penile Cancer

“…This included CDO1, which we also show to be differentially expressed between penile cancer and normal tissue. The inactivation of CDO1 by DNA methylation has recently been implicated in many cancers, including bladder, breast cancer, colon, and lung cancer (32)(33)(34)(35)(36). Cysteine deoxygenase 1 (CDO1) is integral to the biodegradation of toxic cysteine, and reduced CDO1 expression has been shown to increase cell proliferation in vitro, whereas overexpression resulted in decreased tumor growth both in vitro and in vivo (33).…”

“…Integration with publicly available CESC and HNSCC methylation data R statistical software v2.15.1 (35) was used for preprocessing of data and for classic multidimensional scaling (MDS) using principal components analysis (PCA). HPV-specific epigenetic signature and prediction of HPV infection was determined using the shrunken centroid method implemented through the pamr bioconductor package.…”

The epigenetic landscape of renal cancer

“…Overexpression of SLC16A3 correlates with poor patient prognosis and is associated with lower promoter methylation in the tumour compared to less aggressive tumours and normal tissue 119 . CDO1, which is an essential member of the taurine biosynthetic pathway, is involved in the oxidative stress response 120,121 . As in other types of malignancies such as breast cancer 122 , colorectal cancer 123 and prostate cancer 124 , methylation of the CDO1 promoter is associated with poor survival of patients with RCC 118 .…”

Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer

“…These results suggest that a bivalent chromatin structure at the NEFH promoter in MCF10A cells can adequately suppress the expression of NEFH, similar to the poised state of embryonic stem cells, or as previously shown for other genes. 7 Promoter methylation of neurofilament genes NEFH, NEFL, and NEFM is frequent in breast primary tumors and correlates with adverse clinical features…”

“…To characterize the vast amount of DNA methylation data generated, comprehensive functional approaches have been initiated and novel tumor suppressor genes and pathways as well as biomarkers for early detection and prognosis prediction of cancer have been discovered. [2][3][4][5][6][7][8][9][10][11] Neurofilament heavy polypeptide (NEFH) has been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome, a comprehensive approach to define genome-wide functional methylation changes in breast cancer that is based on whole transcriptome expression arrays on breast cancer cell lines after pharmacological inhibition of DNA methylation. 6 NEFH encodes the neurofilament heavy polypeptide and assembles along with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) into 10 nm filamentous structures known as neurofilaments.…”