NEW LINK FOUND BETWEEN BREAST CANCER AND EPIGENETICS
Breast cancer is one of the most common cancers worldwide in females. Researchers from the University of California, Los Angeles (UCLA) found that PIAS1 is linked to breast tumorigenesis. PIAS1 is a transcriptional repressor that has SUMO (small ubiquitin-like modifier) E3 ligase activity. Recently, it had been explored that PIAS1 facilitates a novel epigenetic mechanism to control T cell differentiation. In Liu et al., researchers from the City of Angels reported that PIAS1 SUMO ligase was involved in the progression of breast tumorigenesis. Their studies identified a novel epigenetic mechanism that regulates tumorigenesis through selective gene silencing.
Shuai and team first showed that PIAS1 was upregulated in human breast cancer tissues and important in breast tumorigenesis. When PIAS1 was knocked-down, the survival of MDA-MB231 cells was impaired when grown in stem cell media (SCM) and tumor formation in SCID mice was inhibited in xenograft experiments. They also found that the ALDH+ population that was high in breast tumor initiating cells (TICs) was eliminated and that the formation of mammospheres was also inhibited.
A previous study indicated that Ser90 phosphorylation activated PIAS1 in order to repress the transcription of target genes and that this process was dependent on the SUMO ligase activity of PIAS1. In this paper, Shuai and team found that the growth factors EGF and Heregulin could activate PIAS1 in various breast cancer cell lines. They investigated the significance of PIAS1 Ser90 phosphorylation by doing rescue experiments of PIAS1 knockdown in MDA-MB231 cells. An empty vector, wild type PIAS1, PIAS1 Ser90 mutant, or PIAS1 SUMO ligase defective mutant was introduced in SCM condition. Results showed that only wild type PIAS1 could rescue the PIAS1 knockdown cells from cell death. Additionally, PIAS1 promoted the formation of mammospheres and restored population of ALDH+. This showed that PIAS1 Ser90 phosphorylation and SUMO ligase activity were important for the survival of breast tumor cells.
Next, Shuai and colleagues performed experiments to understand the molecular mechanism of PIAS1-mediated regulation of breast TICs. To find the targets of PIAS1, they focused on the genes that were upregulated in PIAS1 knockdown cells grown in SCM. They found several genes that were upregulated in PIAS1 knockdown cells that are relevant to breast cancer, such as breast cancer DNA methylation signature gene Cyclin D2 (CCND2) and candidate tumor suppressor WNT5A. CCND2 is frequently silenced in human cancers through promoter hypermethylation and the loss of WNT5A is associated with early relapse in invasive ductal breast carcinomas. Since the WNT pathway is known to regulate the self-renewal of stem cells, this UCLA group showed that the formation of mammospheres and tumor growth in vivo were enhanced by the knockdown of WNT5A in PIAS1 knockdown MDA-MB231 cells.
Lastly, the UCLA team studied the PIAS1 epigenetic pathway that operates in breast cancer cells. Previous research reported that CCND2 and WNT5 were hypermethylated in various cancer types. Using chromatin immunoprecipitation (ChIP), the team showed that PIAS1 bound to CCND2 and WNT5A. PIAS1 knockdown also resulted in an increase of the active histone mark histone H3 acetylation (AcH3) and a decrease in histone H3 K9 trimethylation (H3K9me3) in both WNT5A and CCND2 genes. Through analysis of bisulfite sequencing data, the team showed that the methylation levels on CCND2 and WNT5A promoters were reduced in PIAS1 knockdown cells. These results suggest that PIAS1 promotes epigenetic gene silencing by recruiting DNA methyltransferases in breast cancer cells.
Liu et al. reported that, through an epigenetic mechanism, PIAS1 repressed a number of genes that were relevant to breast tumorigenesis. Understanding the molecular specificity involved in the epigenetic gene silencing pathway in PIAS1 may aid in the development of a therapeutic approach for the cure of breast cancer.
Liu B, Tahk S, Yee KM, Yang R, Yang Y, Mackie R, Hsu C, Chernishof V, O’Brien N, Jin Y, Fan G, Lane TF, Rao J, Slamon D, & Shuai K (2014). PIAS1 Regulates Breast Tumorigenesis through Selective Epigenetic Gene Silencing. PloS one, 9 (2) PMID: 24586797
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