OASIS/CREB3L1is epigenetically silenced in human bladder cancer facilitating tumor cell spreading and migrationin vitro

Abstract

CREB3L1 has been recently proposed as a novel metastasis suppressor gene in breast cancer. Our current study highlights CREB3L1 expression, regulation, and function in bladder cancer. We demonstrate a significant downregulation of CREB3L1 mRNA expression (n = 64) in primary bladder cancer tissues caused by tumor-specific CREB3L1 promoter hypermethylation (n = 51). Based on pyrosequencing CREB3L1 methylation was shown to be potentially associated with a more aggressive phenotype of bladder cancer. These findings were verified by an independent public data set containing data from 184 bladder tumors. In addition, immunohistochemical evaluation showed that CREB3L1 protein expression is decreased in bladder cancer tissues as well. Interestingly, protein loss is predominately observed in the nuclei of aggressive tumor cells. Based on in vitro models we clearly show that CREB3L1 re-expression mediates suppression of tumor cell migration and colony growth of high grade and invasive bladder cancer cells. The candidate tumor suppressor and TGF-β signaling inhibitor HTRA3 was furthermore identified as putative target gene of CREB3L1 in both invasive J82 bladder cells and primary bladder tumors. Hence, our data provide for the first time evidence that the transcription factor CREB3L1 may have an important role as a putative tumor suppressor in bladder cancer.

Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers

“…As a stress-activated protein, CREB3L1 resides within the cytoplasm as an endoplasmic reticulum transmembrane protein, which can be processed after trafficking to the Golgi to release an active transcription factor that translocates into the nucleus. As has been noted in bladder cancer tumors [ 20 ], the 41 breast tumor samples that expressed CREB3L1 protein showed two main CREB3L1 localization patterns. Approximately half (n = 19) had predominantly nuclear CREB3L1 protein localization (Fig.…”

“…High-grade breast tumors that still express CREB3L1 typically have mainly cytoplasmic protein localization, which likely would prevent CREB3L1-mediated transcriptional repression of target genes that promote cell growth, survival, migration, invasion, angiogenesis and metastasis [ 25 ]. Similar subcellular localization patterns of CREB3L1 are observed during bladder cancer progression, suggesting a common function for CREB3L1 in at least these two cancer types [ 20 ].…”

“…Our results in TNBC and high-grade tumors are in agreement with a recent study by Rose et al . who found that CREB3L1 gene expression was downregulated in bladder cancer and that the loss of expression was associated with DNA methylation of the gene [ 20 ]. They also reported that DNA methylation was associated with invasive tumor subtypes of bladder cancer.…”

“…Although not specific to breast cancer, CREB3L1, like the other members of the UPR, has also been shown to perform important roles in cancer. Epigenetic downregulation of CREB3L1 mRNA expression by DNA methylation is associated with increased tumor grade and aggressive phenotype in bladder cancer [ 20 ]. Also, CREB3L1 has been shown to be necessary for the chemotherapeutic drug doxorubicin to block cell proliferation and may function as a biomarker in predicting response to therapy [ 21 , 22 ].…”

Maternal HtrA3 optimizes placental development to influence offspring birth weight and subsequent white fat gain in adulthood

“…To date, four mammalian HtrAs (HtrA1-4) have been identified [1][2][3][4][5][6][7] , and their dysregulation is associated with a number of diseases, including cancer, arthritis, neurodegenerative disorders, age-related macular degeneration, and pregnancy diseases [8][9][10][11][12][13][14][15][16][17] . In particular, HtrA1 and HtrA3 have been suggested as tumor suppressors, because they are down-regulated in a number of cancers and this reduction is suggested to promote tumorigenesis [18][19][20][21][22] . HtrA3 down-regulation in lung cancer is believed to occur because cigarette smoking induces methylation of the HtrA3 gene 8 .…”