Research Article: BCAR4 activates GLI2 signaling in prostate cancer to contribute to castration resistance

Date Published: December 04, 2018

Publisher: Impact Journals

Author(s): Zhiping Cai, Yapei Wu, Yao Li, Jizhong Ren, Linhui Wang.


Long non-coding RNAs (lncRNAs) have been found essential for tumorigenesis of prostate cancer (PC), but its role in the regulation of castration-resistant prostate cancer (CRPC) is poorly identified. Here, we showed that a lncRNA, Breast-Cancer Anti-Estrogen Resistance 4 (BCAR4), which plays a pivotal role in the tamoxifen-resistance of breast cancer, was significantly upregulated in CRPC, but not in castration-sensitive prostate cancer (CSPC), compared to normal prostate tissue. High BCAR4 levels in CRPC were correlated with poor patients’ overall survival. Androgen increased growth and migration of androgen receptor (AR)-positive PC346 cells, which was abolished by the antagonist of androgen. Overexpression of BCAR4 in PC346 cells increased cell growth and migration, but turned the cells insensitive to androgen. On the other hand, growth and migration of AR-negative DU145 cells are insensitive to androgen, while depletion of BCAR4 in DU145 cells not only decreased cell growth, but also turned the cells sensitive again to androgen. Moreover, BCAR4 activated GLI2 downstream genes, and correlated with the levels of these GLI2-target genes in CRPC. Depletion of GLI2 abolished the effects of BCAR4 on cell growth and migration. Together, our data suggest that BCAR4 may activate GLI2 signaling in PC to contribute to castration resistance.

Partial Text

Prostate cancer (PC) is a common malignant cancer that affects aged men [1]. The occurrence and development of PC generally depend on the stimulation of androgen [2]. The local advanced patients, patients with metastatic spread of tumors, and patients who relapse after conventional treatment are currently preferred by clinical endocrine therapy, also known as androgen deprivation therapy (ADT) [2]. ADT Includes castration therapy (surgical castration or drug castration), antiandrogen therapy (bicalutamide or flutamide) or combined castration and antiandrogen therapy [3].

Accumulating evidence has implied several ways of lncRNA in control of development of CRPC. First, lncRNA may regulate AR signaling pathway directly. For example, Yang et al. reported that PRNCR1 And PCGEM1, two lncRNAs, can regulate the turnover of AR by forming a cyclic structure of chromatin [19]. Second, some lncRNAs may regulate the metabolism of tumor cells. For example, PCGEM1 can upregulate anaerobic glycolysis, pentose phosphate pathway, lipid metabolism and glutamine metabolism to promote tumor cell proliferation [20]. Third, lncRNAs may participate into the epigenetic regulation of tumor cells. Epigenetic changes in PC may eventually develop the cancer into castration resistance. Specially, HOTAIR, PCAT1 and ANRIL have been reported to bind to the PRC2 complex to inhibit the transcription of the AR gene itself [21]. Last, lncRNAs may interact with miRNA as a “molecular sponge” to absorb a variety of PC-related miRNAs, thereby neutralizing their tumor suppressor function. For example, CDR1as/CiRS-7 contains more than 70 binding sites for miR-7 to strongly inhibit the tumor suppressor function of miR-7 [22].




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