Targeting the DNHD1‑HDAC6 axis inactivates prostate cancer cell aggressiveness in vitro, suggesting potential therapeutic vulnerability

Prostate cancer progression toward an aggressive, therapy‑resistant disease state remains a major clinical challenge, indicating a need to identify novel molecular drivers of such progression and actionable therapeutic targets. The present study analyzed the role of dynein heavy chain domain 1 (DNHD1), a previously uncharacterized regulator of malignancy, in prostate cancer. Integrative transcriptomic analyses across The Cancer Genome Atlas and independent clinical cohorts revealed that DNHD1 is markedly upregulated in advanced‑stage prostate cancer and positively correlated with increasing Gleason scores. Elevated DNHD1 expression was associated with poor overall survival and disease‑free survival, which supports its clinical relevance as a prognostic biomarker. Functional analyses demonstrated that DNHD1 promoted tumor cell proliferation, colony formation, migration and invasion in vitro. Molecular correlation modeling and pathway analyses revealed histone deacetylase 6 (HDAC6) as a key downstream effector of DNHD1. DNHD1 expression was positively correlated with and regulated HDAC6 expression in clinical datasets. Gain‑of‑function and loss‑of‑function experiments further revealed that HDAC6 is required for DNHD1‑mediated oncogenic phenotypes in prostate cancer, positioning HDAC6 as a functional mediator downstream of DNHD1. The DNHD1‑HDAC6 axis was associated with cilium assembly‑related pathways, suggesting a previously unrecognized association between ciliary regulation and prostate cancer progression. HDAC6 inhibition with tubastatin A effectively suppressed DNHD1‑driven tumor growth and motility, as well as increased acetylated α‑tubulin and decreased androgen receptor signaling. These findings indicated a potential therapeutic vulnerability within the DNHD1‑HDAC6 axis. They implied that in prostate cancer, the DNHD1‑HDAC6 axis, a novel regulatory pathway, promotes aggressiveness and that HDAC6 is a targetable mediator of DNHD1‑driven malignancy. This axis can be considered a prognostic indicator and mechanistic foundation for developing targeted therapeutic strategies for advanced prostate cancer.