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Abstract
Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type-1 (SCA1) neurodegenerative disease and some types of cancer; however, the role of CIC in prostate cancer remains unknown. Here we show that CIC suppresses prostate cancer progression. CIC expression was markedly decreased in human prostatic carcinoma. CIC overexpression suppressed prostate cancer cell proliferation, invasion, and migration, whereas CIC RNAi exerted opposite effects. We found that knock-down of CIC derepresses expression of ETV5 and CRABP1 in LNCaP and PC-3 cells, respectively, thereby promoting cell proliferation and invasion. We also discovered that miR-93, miR-106b, and miR-375, which are known to be frequently overexpressed in prostate cancer patients, cooperatively down-regulate CIC levels to promote cancer progression. Altogether, we suggest miR-93/miR-106b/miR-375-CIC-CRABP1 as a novel key regulatory axis in prostate cancer progression.
Highlights
CIC is an HMG box-containing transcriptional repressor evolutionarily conserved from nematodes to humans [1]
Given that several ETS transcription factor genes (ERG and PEA3 group genes) are frequently overexpressed due to chromosomal translocations in prostate cancer cells, thereby contributing to prostate cancer pathogenesis [15], we hypothesized that CIC might suppress prostate cancer progression through repressing expression of PEA3 group genes
We identified cellular retinoic acid binding protein 1 (CRABP1) as a novel CIC target, and provided a molecular basis of how CIC regulates prostate cancer progression
Summary
CIC is an HMG box-containing transcriptional repressor evolutionarily conserved from nematodes to humans [1]. At least two CIC isoforms exist in Drosophila and mammals, CIC-L and CIC-S, which differ in their aminoterminal regions. The longer isoform CIC-L contains a unique amino-terminal region of approximately 900 amino acids in length in mammals [2]. CIC was identified as an interacting protein of ATXN1, the causative protein of SCA1 neurodegenerative disease [5]. Haploinsufficiency of CIC partially rescues ataxia phenotypes in Atxn1154Q knock-in mice, suggesting that CIC facilitates pathogenesis of SCA1 [6]. It is known that Cic hypomorphic (Cic-L-/-) mice have defects in lung alveolarization and bile acid homeostasis [7, 8]
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