Loss of FAM60A disrupts Sin3/HDAC control of the Hippo signaling and promotes oncogenic YAP1 activation

Using immunological, biochemical, CRISPR/Cas9, genomic, and proteomic approaches, we mapped the FAM60A interaction network and its functional impact. We reveal that FAM60A binds directly to HDAC1 to recruit Sin3/HDAC to SIN3A, while a dual domain architecture mediates additional associations with RNA and DNA binding proteins.

CRISPR/Cas9–mediated HDAC1 knockout abolishes the FAM60A–SIN3A interaction, confirming this dependency. Loss of FAM60A triggers widespread transcriptional rewiring, including downregulation of WWC3—a scaffold for LATS1/2 activation. Consequently, YAP1 dephosphorylation and nuclear accumulation shifted cell-cycle dynamics toward G₁ enrichment and conferred resistance to metabolic stress.