Heterochromatin Protein 1α Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer

Abstract

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer arising mostly from adenocarcinoma via neuroendocrine transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathologic feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor and RE1 silencing transcription factor and enriched the repressive trimethylated histone H3 at Lys9 mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management. Heterochromatin proteins play a fundamental role in NEPC, illuminating new therapeutic targets for this aggressive disease. .

HnRNPM is a potential mediator of YY1 which promotes EMT in prostate cancer cells

“…59 NEPC loses the characteristics of the luminal epithelium, making its biological features different from those of ADENO. 60 The NEPC phenotype and molecular characteristics are associated with stronger invasiveness and metastasis, low or absent androgen receptor (AR) expression, RB loss combined with p53 dysfunction, and upregulated expression of neuroendocrine genes such as chromogranin A and neuron-specific enolase. 37,61,62 This transformation causes NEPC to no longer respond to typical AR pathway inhibition (ARPI).…”

Epigenetic modulations and lineage plasticity in advanced prostate cancer

“…11,17,59 Other studies also suggested that neuroendocrine transdifferentiation of PADCs be driven by variable genetic mechanisms such as overexpression of SRRM4, 60 hypoxia-mediated signaling, 43,61 PKC-lambda/iota reduction, 62 and elevated HP1a expression. 63 In addition, tumor-associated macrophages (TAMs) are an important component of tumor microenvironment. Recently Zarif et al 64 showed that TAM can reprogram tumor phenotype and play a major role in the emergence of a neuroendocrine phenotype in prostate cancers.…”

“…Ci et al 63 recently identified 36 heterochromatin-related genes by analysis of patient-derived xenograft, multiple patient cohorts, and genetically engineered mouse models. They showed that NEPCs have a distinctive heterochromatin gene signature compared with PADCs.…”

“…Silencing of HP1a reactivates AR and REST expression and inhibits NEPC tumor growth. 63 The chromodomain of the HP1 proteins recognizes H3K9me3 and this interaction forms the basis for further recruiting of other heterochromatin-associated proteins, thereby initiating chromatin modification and gene silencing. 95 Interestingly DEK1, an epigenetic regulator, was reported to interact directly with HP1a and significantly enhance its binding to trimethylated H3K9 (H3K9me3).…”

Using NEPC cell NCI-H660 for in vitro assays

“…In this protocol, we provide a simple and practical solution to overcome this technical hurdle. This method was employed in our recent study, providing in vitro evidence of the essential function of a gene named HP1α in maintaining NEPC aggressiveness (8).…”