Transcriptional repression of the tumor suppressor DRO1 by AIB1

Abstract

Edited by Angel NebredaKeywords: DRO1 Apoptosis AIB1 Golgi Extracellular matrix a b s t r a c t Using transcriptomic gene expression profiling we found tumor suppressor DRO1 being repressed in AIB1 transgenic mice. In agreement, AIB1 represses DRO1 promoter and its expression levels inversely correlate with DRO1 in several cancer cell lines and in ectopic and silencing assays. Estrogen modulators treatment showed a regulation in an estrogen receptor-dependent fashion. Importantly, DRO1 overexpression resulted in BCLAF1 upregulation, a compelling concept given that BCLAF1 is a death-promoting transcriptional repressor. Additionally, DRO1 shuttles from Golgi to the endoplasmic reticulum upon apoptotic stimuli, where it is predicted to facilitate the apoptosis cascade. Finally, DRO1 repression is an important factor for AIB1-mediated inhibition of apoptosis. Collectively, our results reveal DRO1 as an AIB1-targeted tumor suppressor, providing a novel mechanism for AIB1-dependent inhibition of apoptosis.

DRO1/CCDC80: a Novel Tumor Suppressor of Colorectal Carcinogenesis

“…Consistently, downregulation of DRO1/CCDC80 upon oncogenic activation has been observed in mammary epithelial and carcinoma cells, both overexpressing the oncogene AIB1, and in U2OS osteosarcoma cells transfected with v-H-Ras and v-Src [7]. In contrast, in PC E1A thyroid cells, introduction of polyoma middle-T or v-src oncogenes had no effect on DRO1/CCDC80 expression level [6].…”

“…Converse results on the effect of β-Estradiol on DRO1/CCDC80 expression have been obtained by Ferragud and colleagues. They have shown that addition of β-Estradiol to the medium of human mammary carcinoma cells represses DRO1/CCDC80 expression, whereas treatment with antiestrogens leads to DRO1/CCDC80 induction [7]. Thus, further studies are needed to elucidate the role of DRO1/CCDC80 in mammary carcinogenesis.…”

“…In several studies, DRO1/CCDC80 has been localized throughout the cytoplasm [4, 6, 8, 9, 20•, 25], and it has also been detected at the cytoplasmic membrane [7,26].…”

The role of AIB1 in breast cancer

“…Further investigation revealed that DROI plays an important role in adipogenesis through downregulating Wnt/β-catenin signaling and inducing C/EBPα and PPARγ (75). The expression of DROI was significantly reduced in mouse mammary epithelial cells or human primary cultures overexpressing AIB1 (72). Furthermore, DROI expression levels decreased in MCF-7 cells treated with estrogen but increased when treated with tamoxifen.…”

“…For example, knockdown of AIB1 by siRNA in human chronic myeloid leukemia K562 cells reduces activation of NF-κB signaling, ultimately leading to apoptosis (70), while overexpression of AIB1 in human embryonic kidney 293 (HEK293) cells has the reverse effect (71). A study by Ferragud et al (72) revealed that AIB1 acts as a negative regulator for DROI, a tumor suppressor gene that was first identified as upregulated in brown adipose tissue of mice deficient in bombesin receptor subtype-3 (73). The function of DROI as a tumor suppressor gene was later demonstrated when its expression was shown to be highly reduced in colon and pancreatic cancers (74).…”