Circadian regulator REV-ERBα is a master regulator of tumor lineage plasticity and an effective therapeutic target

TL;DR

This study shows that the circadian regulator REV-ERBα plays a key role in prostate cancer's ability to resist treatment and change its cell type, making it a promising target for new therapies.

Contribution

The study identifies REV-ERBα as a master regulator of tumor lineage plasticity in prostate cancer, revealing a novel mechanism for therapy resistance.

Findings

REV-ERBα is reprogrammed by anti-androgen drugs to drive tumor lineage plasticity.

Pharmacological inhibition of REV-ERBα suppresses tumor growth and lineage plasticity in drug-resistant prostate cancer.

REV-ERBα recruits BRD4 and p300 to promote chromatin accessibility and activation of lineage plasticity genes.

Abstract

Tumor lineage plasticity (LP) is a major mechanism of therapy resistance and metastasis in many solid tumor malignancies including prostate cancer. Better understanding of the process is vital to developing effective therapeutic intervention. Here, we report that drugs targeting the androgen receptor (AR) in prostate cancer induce a functional switch of circadian regulator/nuclear receptor REV-ERBα to act as a master regulator in the initial induction of a network of LP driving factors. Pharmacological or genetic inhibition of REV-ERBα potently blocks the growth of drug-resistant tumors and effectively suppresses tumor LP, thus nominating REV-ERBα as an attractive target for treatment of advanced diseases with LP.

Epigenetic and transcriptional dysregulation plays a fundamental role in tumor lineage plasticity (LP). However, the underlying mechanisms, especially for the initial events of LP development, are still poorly understood. Here, we report that in progression of prostate cancer from adenocarcinoma to treatment-induced neuroendocrine prostate cancer (t-NEPC), anti-androgen receptor (AR) signaling inhibitors (ARSIs) reprogram the function of circadian regulator/nuclear receptor REV-ERBα by switching its target gene programs from kinase signaling and metabolic programs to programs of LP, which includes neurogenesis, stem cell, and epithelial–mesenchymal transition as well as over fifteen LP drivers including POU3F2/BRN2, ASCL1, FOXA2, ONECUT2, and MYCN. Unexpectedly, REV-ERBα facilitates the chromatin occupancy of BRN2, ASCL1, and FOXA1 in their activation of LP programs, thus functioning as a master regulator of ARSI-induced LP driver network. Mechanistically, REV-ERBα induces chromatin accessibility and H3K27ac modification at promoters of LP genes through its recruitment of BRD4 and p300. Overexpression of REV-ERBα alone is sufficient to induce LP and neuroendocrine phenotype and confers resistance to ARSI in adenocarcinoma cells. Loss of REV-ERBα potently inhibits NEPC cell growth and abolishes the expression of LP drivers and gene programs. Pharmacological inhibition of REV-ERBα exhibits high potency in blocking the growth of NEPC tumors including patient-derived xenografts. Our findings reveal that therapy-induced LP development entails a coordinated induction of a network of LP drivers and that REV-ERBα is an unexpected master regulator of the network and a promising therapeutic target for treatment of advanced prostate cancer such as NEPC.

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