YEATS2 promotes DNA repair and induces anoikis resistance by enhancing chromatin accessibility to drive prostate cancer metastasis.

Despite advancements in therapeutic strategies, metastatic prostate cancer (mPCa) remains challenging to treat, with limited clinical efficacy and poor prognosis. Anoikis resistance in tumor cells is crucial for their survival in the vascular system and plays a key role in metastasis. Therefore, investigating the molecular mechanisms of metastasis and anoikis resistance is essential for identifying novel therapeutic targets and strategies. In this study, we found that YEATS domain-containing 2 (YEATS2) plays a critical role in promoting PCa metastasis by suppressing anoikis. We observed that YEATS2 expression was elevated in mPCa and associated with poor clinical outcomes. Knockdown of YEATS2 reduced the metastatic potential of PCa cells both in vivo and in vitro, whereas its overexpression inhibited anoikis and promoted metastasis by upregulating the expression of the DNA damage repair gene RAD50. Mechanistically, YEATS2 increases chromatin accessibility at the RAD50 promoter region by recognizing H3K27ac and subsequently recruits the transcription factor NR2C2. Mirin suppressed lymph node metastasis of PCa cells in vivo. Our study demonstrated a novel function of the YEATS2/NR2C2/RAD50 axis in regulating DNA damage responses and anoikis resistance in PCa metastasis, highlighting an important pathway that drives metastatic progression and offering potential new strategies for treating mPCa.