A SOX9 C-terminal module recruits cBAF to enforce malignant stem-like chromatin plasticity

Cancer initiation is not dictated by mutation alone; premalignant lesions acquire nongenetic cell-state programs that sustain stem-like plasticity and oppose differentiation. SOX9 has emerged as a recurrent regulator of premalignant and malignant epithelial states, including colorectal cancer (CRC), but the mechanism by which SOX9 stabilizes these programs has remained unresolved. Here, we identify the SOX9 C-terminus as a modular cBAF-recruitment element that is required for endogenous enhancer remodeling, can be functionally bypassed by enforced SMARCB1 docking, and sufficient for sgRNA-directed chromatin opening. We find that intrinsically disordered regions (IDRs) within the SOX9 C-terminus physically engage SMARCB1-containing cBAF complexes and recruit them to enhancers of stem-like genes that become selectively accessible during precancerous adenoma formation and remain SOX9-dependent in established CRC. Genome engineering of degron-tagged SOX9 in CRC cells revealed that SOX9 loss reduces cBAF occupancy, promotes enhancer chromatin closure, and activates differentiation, whereas SOX9 restoration reinstates cBAF recruitment, enhancer accessibility, and a stem-like state. The SOX9 C-terminus is required for cBAF binding and chromatin remodeling, while enforced SMARCB1 linkage to C-terminally truncated SOX9 partially restores chromatin accessibility and stem-like behavior in organoids. Finally, we leverage this mechanistic insight to develop a chromatin opening module for engineered targeting (COMET), in which the isolated SOX9 C-terminus is sufficient, when targeted to DNA, to recruit endogenous cBAF and open chromatin. Together, these findings establish the SOX9 C-terminus as a modular SMARCB1/cBAF-recruitment element that links initiating oncogenic stress to enhancer remodeling, malignant cell-state stabilization, and programmable endogenous chromatin remodeler recruitment.