Derepression of Cancer/Testis Antigens in cancer is associated with distinct patterns of DNA Hypomethylation

Abstract

BackgroundThe Cancer/Testis Antigens (CTAs) are a heterogeneous group of proteins whose expression is typically restricted to the testis. However, they are aberrantly expressed in most cancers that have been examined to date. Broadly speaking, the CTAs can be divided into two groups: the CTX antigens that are encoded by the X-linked genes and the non-X CT antigens that are encoded by the autosomes. Unlike the non-X CTAs, the CTX antigens form clusters of closely related gene families and their expression is frequently associated with advanced disease with poorer prognosis. Regardless however, the mechanism(s) underlying their selective derepression and stage-specific expression in cancer remain poorly understood, although promoter DNA demethylation is believed to be the major driver.MethodsHere, we report a systematic analysis of DNA methylation profiling data from various tissue types to elucidate the mechanism underlying the derepression of the CTAs in cancer. We analyzed the methylation profiles of 501 samples including sperm, several cancer types, and their corresponding normal somatic tissue types.ResultsWe found strong evidence for specific DNA hypomethylation of CTA promoters in the testis and cancer cells but not in their normal somatic counterparts. We also found that hypomethylation was clustered on the genome into domains that coincided with nuclear lamina-associated domains (LADs) and that these regions appeared to be insulated by CTCF sites. Interestingly, we did not observe any significant differences in the hypomethylation pattern between the CTAs without CpG islands and the CTAs with CpG islands in the proximal promoter.ConclusionOur results corroborate that widespread DNA hypomethylation appears to be the driver in the derepression of CTA expression in cancer and furthermore, demonstrate that these hypomethylated domains are associated with the nuclear lamina-associated domains (LADS). Taken together, our results suggest that wide-spread methylation changes in cancer are linked to derepression of germ-line-specific genes that is orchestrated by the three dimensional organization of the cancer genome.

Profiling cancer testis antigens in non–small-cell lung cancer

“…Indeed, hypomethylation-associated CTA expression was observed for established X chromosomal CTAs and novel non-X chromosomal CTAs in around one-third of our NSCLC CTA list. This is in line with previous studies suggesting that epigenetic regulation is one major regulatory mechanism of CTA activation (35,42,43).…”

Proteomic analysis reveals that MAEL, a component of nuage, interacts with stress granule proteins in cancer cells

“…We found that the human MAEL gene is only expressed in germ cells of the testis among normal tissues, but is expressed in various human cancer cell lines such as breast cancer MDA-MB-231 cells and colorectal cancer SW480 cells. Like most of the CT genes (15,16), the expression of the MAEL gene is activated by hypomethylation in cancer (12). Kim et al (17) analyzed the methylation profile of 27,578 CpG sites spanning >14,000 genes in colorectal cancer and adjacent normal mucosa, and found that among the genes tested, MAEL and SFT2D3…”

Cancer/Testis Antigen PASD1 Silences the Circadian Clock

“…PASD1 is not expressed in cells of somatic origin unless it has been de-repressed due to malignant transformation (Kim et al, 2013). The circadian clock is frequently disrupted in cancer, allowing cells to escape its daily temporal control of regulated processes and facilitate tumor growth (Filipski and Lévi, 2009; Sahar and Sassone-Corsi, 2009; Takahashi et al, 2008).…”