Regulation of the Antioxidant Response by MyoD Transcriptional Coactivator in Castration-resistant Prostate Cancer Cells.

Objective: To reveal the potential role of the basic helix-loop-helix myogenic transcription regulator MyoD in the regulation of castration-resistant prostate cancer.

Methods: Expression level of MyoD was assessed in prostate cancer tissues using quantitative reverse transcription polymerase chain reaction and immunohistochemistry and in experimentally induced castration-resistant LNCaP/R cells using quantitative reverse transcription polymerase chain reaction and immunoblotting. Effect of MyoD knockdown on LNCaP/R cell progression was determined by assessing cell proliferation, apoptosis, and colony formation rate. The effect of MyoD knockdown on the oxidative stress state in PC3 cells was determined by assessing antioxidant response gene expression and glutathione synthetase-to-glutathione ratio. Finally, the functional link between the nuclear factor erythroid-derived 2-related factor 1 (NRF1) and the regulation of antioxidant response element-driven transcription by MyoD was studied at both molecular and functional levels.

Results: MyoD expression was significantly upregulated in hormone-refractory prostate cancer tissues and in experimentally induced castration-resistant LNCaP/R cells, and MyoD knockdown effectively impaired LNCaP/R cell proliferation and promoted apoptosis under androgen-depleted condition. Moreover, MyoD enhanced the glutathione production and protected against oxidative stress by positively regulating a cluster of antioxidant genes known to be the downstream targets of NRF1. Mechanistically, MyoD could augment the antioxidant response element-driven transcription in an NRF1-dependent manner, and the stimulatory effect of MyoD on the antioxidant response was substantially compromised in the presence of NRF1 small interfering RNA treatment.

Conclusion: We have identified an unexpected collaboration between MyoD and NRF1 under androgen-depleted condition, which may serve as an important adaptive mechanism during the pathogenesis of castration-resistant prostate cancer.