Tumorigenesis leads to the dedifferentiation of some cancer cells partly resemble stem cells. The maintenance circuitries and epigenetic regulatory complexes that regulate this stem cell-like state known as cancer stem cells (CSCs) are largely unclear. Here we aimed to find strategies for eliminating CSCs in pancreatic cancer (PDAC), one of the most metastatic and lethal cancers in human. Proteomic analyses of SMAD2/3 cofactors and screening of CSC self-renewal regulators uncovered BAZ2A and SUV39H1 as therapeutic targets of CSCs that cooperate with TGFβ/ACTIVIN-SMAD2/3 signalling in gene expression regulation. We show that Cyclin Dependent Kinase Inhibitor (CDKI) loci p14/p16 and p15 are silenced in CSCs by SMAD2/3-BAZ2A-SUV39H1 complex, and inhibiting BAZ2A and SUV39H1 reactivates silenced p14/p16/p15 that helps eliminating CSCs. Furthermore, the TGFβ/ACTIVIN signalling maintains a bivalent poised chromatin and enhancer-promoter 3D looping on CDKI, EMT and ABCC loci through SMAD2/3-SNON-PRC2-TrxG cooperating with OCT4/SOX2/NANOG. Elevated TGFβ/ACTIVIN signalling forms a positive feedback with p21/p57 that promotes a quasi-mesenchymal state of CSCs with increased EMT and higher G0 phase habitance that elevates CSC chemoresistance. Collectively, our study uncovers mechanisms how cell cycle regulation is hijacked in CSCs for supporting cellular plasticity, and how to circumvent this mechanism with combined treatment for targeted therapies.