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

Authors

• Jeyaluxmy Sivalingam, LSU Health-Shreveport, Shreveport, LA
• Kaleigh Ballagh, LSU Health-Shreveport, Shreveport, LA
• Kyung Hyun Cho, LSU Health-Shreveport, Shreveport, LA
• Yingli Shi, LSU Health-Shreveport, Shreveport, LA
• Lin Li, LSU Health-Shreveport, Shreveport, LA
• Preston Barron, LSU Health-Shreveport, Shreveport, LA
• Michael S. Lan, LSU Health Sciences Center - New OrleansFollow
• Omar E. Franco, LSU Health-Shreveport, Shreveport, LA
• Xiuping Yu, LSU Health-Shreveport, Shreveport, LA

Document Type

Article

Publication Date

7-1-2026

Publication Title

Neoplasia

Abstract

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.

First Page

101307

PubMed ID

42001796

Volume

77

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Sivalingam, Jeyaluxmy; Ballagh, Kaleigh; Cho, Kyung Hyun; Shi, Yingli; Li, Lin; Barron, Preston; Lan, Michael S.; Franco, Omar E.; and Yu, Xiuping, "A MYC family switch: L-MYC drives and maintains neuroendocrine lineage programs in prostate cancer" (2026). School of Graduate Studies Faculty Publications. 590.
https://digitalscholar.lsuhsc.edu/sogs_facpubs/590
10.1016/j.neo.2026.101307