2026-01-07 スイス連邦工科大学ローザンヌ校(EPFL)
© EPFL/iStock (Panuwat Dangsungnoen)
<関連情報>
- https://actu.epfl.ch/news/cracking-the-code-for-prostate-cancer/
- https://aacrjournals.org/cancerres/article-abstract/doi/10.1158/0008-5472.CAN-25-2053/770907/The-Histone-Methyltransferase-KMT2D-is-a-Critical?redirectedFrom=fulltext
ヒストンメチルトランスフェラーゼKMT2Dは去勢抵抗性前立腺癌における細胞系可塑性と治療反応の重要なメディエーターである The Histone Methyltransferase KMT2D is a Critical Mediator of Lineage Plasticity and Therapeutic Response in Castration Resistant Prostate Cancer
Srushti Kittane;Erik Ladewig;Taibo Li;Jillian R. Love;Ryan Blawski;Yangzhenyu Gao;Amaia Arruabarrena-Aristorena;Peihua Zhao;Susan L. Dalrymple;Huayang Liu;Xinyu Guo;Mirna Sallaku;Nachiket Kelkar;Liliana Garcia-Martinez;Javier Carmona Sanz;Wanlu Chen;Candice Stoudmann;Laura Baldino;Milad Razavi-Mohseni;Ingrid Kalemi;Michael A. Beer;Pau Castel;W. Nathaniel Brennen;Maurizio Scaltriti;Lluis Morey;Emiliano Cocco;Hongkai Ji;Ho Man Chan;Alexis Battle;Christina S. Leslie;Wouter R. Karthaus;Eneda Toska
Cancer Research Published:December 11 2025
DOI:https://doi.org/10.1158/0008-5472.CAN-25-2053
Abstract
Castration-resistant prostate cancer (CRPC) is largely dependent on the androgen receptor (AR) for growth and often exhibits hyperactive PI3K signaling, most frequently due to PTEN loss. Therapeutic pressure from anti-AR therapies can induce trans-differentiation toward an AR-independent phenotype. Recently, different subtypes of AR-independent CRPC have been redefined, with the stem cell-like (SCL) subtype emerging as one of the most prevalent. Elucidation of the epigenetic mechanisms controlling the maintenance of these distinct CRPC cell states could pave the way for effective combinatorial therapies for CRPC. In this study, we identified a key role for the histone methyltransferase KMT2D in establishing the chromatin competence necessary for the recruitment of AR and FOXA1 transcription factors (TFs) that are essential for the AR transcriptional output in AR-dependent CRPC cell lines, patient derived organoids, and patient samples. Unexpectedly, KMT2D maintained the identity of the AR-low CRPC-SCL subtype and controlled activity of AP-1 TFs such as FOSL1, which acts as a master regulator of this subtype. Single cell transcriptomics and chromatin assays underscored the role of KMT2D in sustaining a mixed lineage cell state via AP-1 and FOXA1. The combined suppression of PI3K/AKT and KMT2D reduced cell proliferation in prostate cancer cells and patient-derived organoids in both CRPC-AR and CRPC-SCL subtypes. Altogether, these results unveil KMT2D as a major mediator of the epigenetic landscape in subtype-specific CRPC, contributing to tumor growth and therapeutic response.
