What question did this study set out to answer?

To investigate the role of the TIP60 acetyltransferase complex in neuroendocrine prostate cancer (NEPC) and its regulatory functions on MYCL.

January 23, 2026

Abstract PR036: The TIP60 acetyltransferase complex is a critical dependency in neuroendocrine prostate cancer through its role as a critical coactivator of MYCL downstream of ASCL1

Key Points

To investigate the role of the TIP60 acetyltransferase complex in neuroendocrine prostate cancer (NEPC) and its regulatory functions on MYCL.
Characterization of isogenic PRAD and NEPC mouse tumoroid models using human-relevant driver mutations.
CRISPR screens targeting transcription factors and coactivators to identify essential components for NEPC survival.
Assessment of TIP60's acetylation activity and chromatin binding in NEPC models.
Identification of TIP60 as a critical coactivator of MYCL in NEPC.
Demonstrated chromatin redistribution of FOXA1 and TIP60 to NEPC-specific enhancers.
Targeted degradation of TIP60 showed over 500-fold dependency in NEPC compared to normal prostate tissue.

Abstract

Abstract Neuroendocrine prostate cancer (NEPC) is an increasingly prevalent manifestation of acquired resistance to next generation AR signaling inhibitors (ARSI), that arises via transformation from advanced prostate adenocarcinoma (PRAD) through a mechanism called lineage plasticity. Through characterization of isogenic PRAD and NEPC mouse tumoroid models generated using human-relevant driver mutations (Pten-/-;Rb1-/-;Trp53-/-), we revealed an extensive epigenetic reprogramming in NEPC versus PRAD, particular at enhancers. CRISPR screens focused on TFs and coactivators revealed a NEPC lineage TF survival network comprised of ASCL1, NFIB, SOX1/11, FOXA1/2 and MYCL with exquisite dependency on the TIP60 acetyltransferase complex. During the PRAD-to-NEPC transition, FOXA1, NFIB and TIP60 chromatin binding redistributes to NEPC specific enhancers, resulting in expression of NEPC target genes in a coordinate fashion with ASCL1 functioning as master regulator, culminating in activation of MYCL. MYCL then directly recruits the TIP60 complex to target sites, where it acts as a requisite MYCL coactivator for target gene activation for NEPC growth/survival. The acetyltransferase activity of TIP60 and acetylation of its substrate H2A. Z are both required for NEPC survival, as well as two chromatin reader subunits of the TIP60 complex, BRD8 and YEATS4. Targeted chemical degradation of TIP60 revealed 500-fold dependency in NEPC relative to normal prostate, credentialing the TIP60 complex as a potential therapeutic target in NEPC. Citation Format: Zhen Sun, Jimmy L. Zhao, Wazim M. Ismail, Zahra F. Khan, Teng Han, Subhiksha Nandakumar, Serina Young, Matthew Lange, Richard Koche, Alexandre Gaspar-Maia, Charles L. Sawyers. The TIP60 acetyltransferase complex is a critical dependency in neuroendocrine prostate cancer through its role as a critical coactivator of MYCL downstream of ASCL1 abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr PR036.

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