YAP activated SATB2 amplifies anti-oxidative capacity and promotes tumor progression as a coactivator of NRF2 in renal cell carcinoma

Aberrant epigenetic reprogramming contributes to progression of renal cell carcinoma (RCC). However, the role of Nuclear matrix-associated proteins (NMPs) in RCC remains unclear. Here we found that SATB2 was up-regulated in RCC samples and correlated with inferior prognosis. SATB2 inhibition suppressed RCC growth and self-renewal capacities. YAP/TEAD4 activated SATB2 expressions and depended on SATB2 to enhance cell proliferation. Transcriptome analysis implicated that SATB2 regulates NRF2 downstream targets without altering NRF2 levels. Integrated CUT&Tag and ATAC-seq demonstrated that SATB2 coordinated with NRF2 to drive the enhancer-promoter interaction, amplifying the transcriptional activity. SATB2 recruits the subunits of SWI/SNF complex, like BRD7 or BRG1, to sustain the DNA accessibility. Increased SATB2 triggered chromatin remodeling into configurations that render RCC more addicted to SATB2 deficiency. Thus, targeting SATB2 is an effective strategy to suppress the YAP-high RCC.