ASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer

Abstract

Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and differentiation toward neuroendocrine lineage. Here, we find that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identify the proneuronal transcription factor ASCL1 motif to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 through UHRF1/AMPK axis and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPIs, governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs.

The 28th Annual Prostate Cancer Foundation Scientific Retreat report

“…BRN2 was identified as a driver and promising therapeutic target in NEPC. Some of these data have been published 46–48 . Further development of the the first‐in field BRN2 inhibitor is underway.…”

“…Some of these data have been published. [46][47][48] Further development of the the first-in field BRN2 inhibitor is underway. SKCC is located in Philadelphia, Pennsylvania.…”

Role of transcription factors and chromatin modifiers in driving lineage reprogramming in treatment-induced neuroendocrine prostate cancer

“…ASCL1 positively regulate neural progenitor differentiation and there is a strong correlation between ASCL1 expression and acquisition of NE-like features ( Narayanan et al, 2019 ). ASCL1 upregulation is an early event following AR signaling suppression ( Nouruzi et al, 2022 ). Hence, ASCL1 is also regarded as an efficient marker for aggressive phenotype and malignant cancer progression ( Vias et al, 2008 ).…”

“…This strongly suggests that ASCL1 is highly responsive to androgen and maybe regulated by the AR signaling axis ( Fraser et al, 2019 ). A recent study shows that targeting ASCL1 switches NE lineage to luminal epithelial state ( Nouruzi et al, 2022 ). ASCL1 is enriched in hyper-accessible regions and functions predominantly by disrupting the epigenetic landscape of cancer cells and plays a pivotal role in the early chromatin remodeling in driving PCa NED.…”

Polycomb Directed Cell Fate Decisions in Development and Cancer

“…In addition, ATAC-seq and RNA-seq analysis demonstrated that ASCL1 , SOX2 and NEUROD1 expression are shared master regulators between neuroendocrine cancers. ASCL1 and NEUROD1 expressions are mutually exclusive, and are drivers of intra-tumoral heterogeneity, a program that occurs due to distinct H3K27ac genome-wide de novo deposition in SCLC and PCa [ 192 , 193 ]. These data support the association of de novo cis-regulatory elements harboring H3K27ac as a determinant of lineage plasticity in neuroendocrine carcinomas.…”