Kinnaird, A. | Search bioRxiv

bioRxiv2026

Pharmacologic Targeting of ZNF281 Suppresses Metastatic Prostate Cancer Beyond Androgen Receptor Dependence

Metastatic prostate cancer remains a lethal disease, with most treatments focusing on the androgen receptor (AR) axis. We identified the zinc finger protein 281 (ZNF281) as a previously unrecognized driver of metastatic prostate cancer that promotes both AR-related transcriptional output and distinct AR-independent tumor-promoting pathways. It increases AR expression and acts as a coactivator to promote AR transcriptional activity. Independent of AR, ZNF281 promotes prostate cancer by upregulating SMURF1 to sustain tumor growth and by promoting SNAIL-mediated metastasis. We developed an orally bioavailable, ZNF281 Interfering Molecule (Oral ZIM) that disrupts its DNA binding and AR protein interaction. Knockout of ZNF281 as well as treatment with oral ZIM potently inhibited prostate cancer growth and metastasis in orthotopic xenograft models of castration-sensitive and castration-resistant prostate cancers (without detectable systemic toxicity), and ZIM outperformed enzalutamide treatment in patient-derived prostate cancer organoids.

cancer biology↗

bioRxiv2025

Hyperacute Response Proteins (HARPs) synthesized on γ-tubulin-FTO-MARK4 translation microdomains upon exposure to stress, regulate stressresponse in cancer.

Compared to normal, cancer cells are particularly resistant to stress, and their immediate response to stress is critical for their subsequent multilayered adaptation programs which pose a major clinical challenge. With unbiased proteomics and transcriptomics analysis, we identified a list of HARPs synthesized from pre-existing mRNAs within 20 min of diverse stresses in A549 cancer cells, despite the known suppressed global translation in stress. HARP mRNAs were translated on microtubule-associated translation microdomains (MATMs) located on {gamma}-tubulin, that host FTO and specialized cytoskeletal ribosomes, structurally and functionally distinct from ER and cytosolic ribosomes. FTO exited the nucleus immediately after stress and was activated by the microtubule-associated stress kinase MARK4 via T6 phosphorylation. Activated FTO demethylated a translation-inhibiting mRNA methylation (m6A) signature, facilitating compartmentalized HARP translation on MATMs, while non-HARP mRNA remained inhibited. FTO or MARK4 inhibition suppressed HARP synthesis and increased apoptosis post various stresses, including chemotherapy. These data were confirmed in 4 additional cancer cell lines and normal fibroblasts. Using the Protein Atlas database, we found that high levels of our identified HARPs had on average a 35% decrease on patient 5-year survival in prevalent and resistant cancers (breast, lung, liver, pancreas). {gamma}-tubulin, FTO and MARK4 are therapeutic targets for many cancers, through their ability to comprehensively promote HARPs translation, a potential Achilles heel for cancers resistance to physiologic or therapeutic stress, offering a new window in stress biology.

cancer biology↗