A MYC family switch: L-MYC drives and maintains neuroendocrine lineage programs in prostate cancer

• First report of MYCL expression and function in NEPC. • MYCL up and MYC down, lineage-associated MYC switch in PCa. • MYCL activation reflects a permissive epigenetic state. • MYCL suppresses AR and drives neuroendocrine-like reprogramming. • MYCL depletion restores adenocarcinoma genes, including MYC. Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype that emerges through lineage plasticity following androgen receptor pathway inhibition. Although MYC family oncogenes are central to prostate cancer progression, the role of MYCL (L-MYC) in NEPC has remained poorly defined. Here, we show that MYCL is selectively and robustly upregulated in NEPC patient samples and experimental models, whereas MYC is concurrently suppressed and MYCN remains low, revealing a lineage-associated MYC family switch. MYCL expression strongly correlates with the neuroendocrine lineage regulators ASCL1 and INSM1 and inversely with adenocarcinoma-associated genes. Functionally, MYCL overexpression suppresses androgen receptor signaling, induces neuroendocrine-like transcriptional reprogramming, and remodels cytoskeletal and adhesion pathways associated with cellular plasticity, whereas MYCL knockdown disrupts neuroendocrine lineage identity and restores adenocarcinoma-associated gene expression, including MYC. Mechanistically, MYC suppression is associated with transcriptional regulation by ASCL1, while MYCL upregulation appears to occur within a permissive epigenetic landscape rather than through genomic amplification. Together, these findings identify MYCL as a lineage-specific regulator that drives and maintains neuroendocrine identity and define a MYC family regulatory switch in which MYCL replaces MYC to stabilize neuroendocrine lineage programs in advanced prostate cancer.