Serotonin Modulates Lineage Plasticity in Neuroendocrine Prostate Cancer via Epigenetic Reprogramming

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer known for therapy resistance and lineage plasticity.
• The role of metabolic and signaling molecules in NEPC cell fate transitions is not fully understood.
• NE tumors are characterized by the production and accumulation of serotonin, a neurotransmitter with diverse physiological functions.

Purpose of the Study:

• To investigate the role of a tumor-intrinsic serotonin axis in driving NEPC lineage commitment and progression.
• To elucidate the molecular mechanisms by which serotonin influences NEPC development.
• To evaluate the therapeutic potential of targeting the serotonin pathway in NEPC.

Main Methods:

• Identification of serotonin synthesis and reuptake pathways in NEPC cells, including aromatic L-amino acid decarboxylase (DDC) and SLC6A4.
• Analysis of the impact of intracellular serotonin on histone modifications, specifically histone serotonylation at H3K4me3Q5.
• Assessment of downstream gene expression changes and androgen receptor signaling.
• Pharmacological inhibition of DDC using carbidopa in genetically engineered and patient-derived xenograft models of NEPC.

Main Results:

• A tumor-intrinsic serotonin axis, involving endogenous serotonin synthesis via DDC and reuptake via SLC6A4, was identified as a key driver of NEPC.
• High intracellular serotonin levels promote histone serotonylation at H3K4me3Q5, altering the chromatin landscape and gene expression.
• This epigenetic reprogramming drives NE differentiation and is associated with suppressed androgen receptor signaling.
• Pharmacological inhibition of DDC with carbidopa significantly reduced tumor growth and prolonged survival in preclinical NEPC models.

Conclusions:

• The serotonin axis is a critical regulator of NEPC lineage commitment and progression.
• Histone serotonylation represents a novel, druggable vulnerability in NEPC.
• Targeting serotonin synthesis with DDC inhibitors like carbidopa shows therapeutic promise for NEPC treatment.