Role of BCAR4 in prostate cancer cell autophagy

Background: Increased autophagy of prostate cancer (PC) cells contributes to their resistance to chemotherapy. Recently, we reported that a long non-coding RNA (lncRNA)-breast-cancer anti-estrogen resistance 4 (BCAR4)-is highly expressed in PC and contributes to castration resistance through activation of GLI2 signaling. However, the role of BCAR4 in the regulation of PC cell autophagy is unknown and is the subject of the current study. Methods: BCAR4 and Beclin-1 levels and the alteration in autophagy pathway genes were assessed in PC using a public database and in our own clinical specimens. The correlation between BCAR4 and Beclin-1 levels in PC and PC cell lines was determined and their regulatory relationship was assessed by overexpression and knockout assay. The final effect on autophagy was measured by microtubule-associated protein 1A/1B-light chain 3 (LC3) levels. The mechanism that underlies the control of Beclin-1 by BCAR4 was analyzed by cancer database and gain-of-function and loss-of-function approaches. Results: BCAR4 and Beclin-1 were both upregulated in PC and were positively correlated. BCAR4 directly activated Beclin-1 at transcriptional level, which subsequently increased the ratio of LC3 II to LC3I to augment PC cell autophagy. Beclin-1 did not control levels of BCAR4. Mechanically, BCAR4 and Beclin-1 shared several targeting microRNAs, among which miR-15 and miR-146 appeared to be the mediators of the effects of BACR4 on Beclin-1. Conclusions: BCAR4 may enhance PC cell autophagy through altering miRNA-regulated Beclin-1 expression in PC.

Automated summary

The study found that BCAR4 and Beclin-1 are both upregulated in prostate cancer and positively correlated. BCAR4 enhances autophagy in PC cells by activating Beclin-1, while Beclin-1 does not control levels of BCAR4. The regulatory relationship between BCAR4 and Beclin-1 is mediated by miR-15 and miR-146.