In summary, we identified ASH1L as a bona fide epigenetic oncoprotein and a promising therapeutic target in metastatic cancers, uncovered its cancer cell-intrinsic and extrinsic roles in metastatic progression and bone niche remodeling, and shed light on ASH1L-targeted therapy in PCa and other malignancies with high metastasis rates. Here, ASH1L is linked to cancer.