Reciprocal negative feedback regulation of ATF6a and PTEN promotes prostate cancer progression

Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6a, via interacting to de-phosphorylate ATF6a and consequently inhibiting its nuclear translocation. Conversely, ATF6a promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6a and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6a inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6a as a therapeutic vulnerability in PTEN dysfunctional PCa.

Automated summary

This study reveals an inverse correlation between PTEN expression and unfolded protein response (UPR) signature score in prostate cancer. PTEN suppresses the activity of ATF6a by de-phosphorylating and inhibiting its nuclear translocation, while ATF6a promotes PTEN degradation through inducing CHIP expression. Inhibition of ATF6a in combination with AKT inhibitor shows promising anti-tumor effects. This study highlights ATF6a as a therapeutic target in PTEN dysfunctional prostate cancer.