Loss of EHF facilitates the development of treatment-induced neuroendocrine prostate cancer

Abstract

The rising of a highly aggressive subtype of castration-resistant prostate cancer (CRPC) named treatment-induced neuroendocrine prostate cancer (t-NEPC) after androgen deprivation therapy (ADT) is well known for its features of the neuroendocrine differentiation (NED) and androgen receptor (AR) independence. However, t-NEPC is still largely unknown. Here, we found that EHF is notably depressed in t-NEPC tumors, patient-derived xenografts, transgenic mice, and cell models. Results from cell lines uncovered that ADT represses EHF expression, which is required for the ADT-induced NED. Mechanism dissection revealed that ADT decreases the EHF transcription via relieving the AR binding to different androgen-responsive elements, which then promotes the expression and enzymatic activity of enhancer of zeste homolog 2 (EZH2), consequently catalyzing tri-methylation lysine 27 of histone H3 for transcriptional repression of its downstream genes to promote the NED. Furthermore, preclinical studies from cell and mice models proved that recovery of EHF expression or using EZH2 inhibitor can attenuate aggressive properties of CRPC cells, hinder the progression of t-NEPC, and promote the response of CPRC cells to enzalutamide. Together, we elucidate that the ADT/AR/EHF/EZH2 signaling is required for the ADT-enhanced NED and plays a critical role in the progression of t-NEPC.

Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

“…Anyhow, the one-carbon metabolism has also been implied in the pathogenesis of the highly resistant to treatment neuroendocrine histotype of prostatic cancer (NEPC) [83][84][85][86] since the de-regulation of protein kinase C (characteristic in NEPC) upregulates serine biosynthesis and SAM intracellular levels which allow the epigenetic reshaping of this peculiar type of cancer [87][88][89].…”

Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs

“…EHF deficiency or loss induces an epithelial-to-mesenchymal transition (EMT) and endows epithelial prostate cells with stem-like features and tumour-initiating and metastatic properties [126]. Recently, EHF loss has been demonstrated to facilitate the development of treatment-induced NEPC via transcriptional de-repression of EZH2 and LIN28B and consequential deregulation of let-7 miRNAs expression and its maturation [127][128][129].…”

Focus on the tumor microenvironment: A seedbed for neuroendocrine prostate cancer

“…Patients with PCa may nonetheless acquire resistance to ARPIs. Neuroendocrine differentiation (NED) occurrence and neuroendocrine prostate cancer (NEPC) formation are vital mechanisms of resistance to ARPIs (Long et al, 2021). Essentially, NEPC is a representative type of recurrent tumor with lineage change developing under the survival pressure from targeted therapies.…”