Novel mechanism of androgen receptor regulation through switching by long non-coding RNA LINC01126

Abstract

Long non-coding RNAs (lncRNAs) are molecules with over 200 nucleotides that play regulatory roles in several physiological and pathological processes at the transcriptional and post-transcriptional levels.¹ Altered lncRNA expression has been linked to abnormal tumour cell apoptosis, migration, invasion and proliferative activity. Several lncRNAs have been identified as crucial regulators of castration-resistant prostate cancer (CRPC) and drug resistance.^{2, 3} In this issue, Cai et al. report the role of lncRNA LINC01126 in CRPC by regulating the switch between O-GlcNAcylation and phosphorylation of the androgen receptor (AR).⁴ The authors found that LINC01126 is an AR-repressed lncRNA that is highly expressed in CRPC. AR-targeted therapies upregulated LINC01126 expression by relieving transcriptional repression by AR. In addition, lncRNA LINC01126 overexpression activated AR signaling without androgen, conferring drug resistance to AR-targeted therapies in prostate cancer cells in vitro and in vivo, and was correlated with poor prognosis. Furthermore, lncRNA LINC01126-targeting antisense oligonucleotides (ASOs) substantially inhibited CRPC cells in vitro, showing potential as a therapeutic target in patients with CRPC.

The AR is activated upon ligand binding to the C-terminal domain followed by homodimerization, nuclear translocation, and DNA binding to target genes. This study revealed a novel mechanism regulating AR activity through post-translational modification by switching between O-GlcNAcylation and phosphorylation of AR. AR signalling is a critical promoter of treatment resistance to AR-targeting therapies including androgen deprivation therapy and AR signalling inhibitors; CYP17 inhibitor abiraterone and second-generation antiandrogens including enzalutamide, apalutamide and darolutamide.⁵ The argument put forth by authors that LINC01126 enhances the activity of AR, thereby contributing to treatment resistance, is plausible.

Furthermore, some areas require further investigation, some of which have been highlighted by the authors themselves. First, in aberrantly AR-activated CRPC, LINC01126 should be suppressed as it was found to be downregulated by AR activation. However, LINC01126 was increased in CRPC, and its underlying mechanism warrants further investigation. Second, the authors emphasized that LINC01126 regulated the AR nuclear translocation through the phosphorylation of AR S81. We have previously reported that the acetylation in the nuclear localization signal sequence within the hinge region of AR is critical in the AR translocation regardless of androgen levels.⁶ Also, LINC01126-regulated phosphorylation of AR S81 does not require ligand binding. Then, the mechanical associations between the phosphorylation in the AR S81 and the acetylation in the AR hinge region as well as ligand binding need to be revealed. Third, although the effects on the O-GlcNAcylation of AR and the phosphorylation of AR S81 were indicated using exogenous AR V7 in LNCaP cells, the effect of LINC01126 on endogenous AR variants in 22Rv1 cells was not examined at all. It is crucial to assess the potential of LINC01126-targeting therapy in AR variants-dependent prostate cancer, observed in nearly half of CRPC.

In addition, several inconsistent results have been reported in this study. First, the authors have shown that the effect of LINC01126 on aggressive behaviour in prostate cancer was dependent on AR activation. However, heightened AR signalling failed to expedite prostate cancer proliferation in normal androgen conditions, a phenomenon attributed to the saturation model of AR signalling, as supported by experimental data from AR overexpression.^{7, 8} Second, the authors showed that lncRNA LINC01126-targeting ASOs have great potential for use in clinical settings. However, further research is needed to confirm these findings, as the experiments using LINC01126-targeting ASOs were only conducted in in vitro and have yet to be tested in vivo. The in vivo experimentation is necessary for the development of LINC01126-targeting therapies. However, despite previous reports demonstrating the repression of targeted lncRNAs by ASOs, the expected impact of ASO targeting LINC01126 on its repression was not observed in this case.⁹ Thus, the results of the experiments using ASO should be interpreted cautiously.

Thus, this study suggests a novel mechanism of AR regulation through the switch between O-GlcNAcylation and phosphorylation by lncRNA LINC01126. However, these findings need to be confirmed and further explored before the development of clinical trials.

Drs. Blas and Shiota contributed to the preparation and collection of original literature and figures and the writing and editing of the manuscript.

The authors declare no conflict of interest.

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