Funding
Huadong medicine Joint Funds of the Zhejiang Provincial Natural Science of Foundation
The construction of Key projects by Zhejiang Provincial Ministry
Zhejiang Province Chinese Medicine Modernization Program
The Key project of Scientific Research Foundation of Chinese Medicine
The Key project of Zhejiang Science and Technology Department
The Key project of Basic Scientific Research operating Funds of Hangzhou medical college
Foundation for Innovative Research Groups of the National Natural Science Foundation of China
Natural Science Foundation of Shanghai (Shanghai Natural Science Foundation)
Shanghai Hospital Association, Clinical application management project for antitumor project
the Research Funds of Xuhui District Central Hospital
ARTICLE ABSTRACT
Aberrant epigenetic reprogramming contributes to the progression of renal cell carcinoma (RCC). Elucidation of key regulators of epigenetic reprogramming in RCC could help identify therapeutic vulnerabilities to improve treatment. Here, we report upregulation of the nuclear matrix-associated protein, special AT-rich binding protein-2 (SATB2), in RCC samples, which correlated with poor prognosis. SATB2 inhibition suppressed RCC growth and self-renewal capacities. YAP/TEAD4 activated SATB2 expression and depended on SATB2 to enhance cell proliferation. Transcriptome analysis implicated that SATB2 regulates NRF2 downstream targets to suppress oxidative stress without altering NRF2 levels. Integrated chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin using sequencing analyses demonstrated that SATB2 coordinated with NRF2 to drive enhancer–promoter interactions, amplifying transcriptional activity. SATB2 recruited SWI/SNF complex subunits, including BRD7 or BRG1, to sustain DNA accessibility. Increased SATB2 triggered chromatin remodeling into configurations that rendered RCC more sensitive to SATB2 deficiency. Moreover, SATB2 ablation promoted the sensitivity of RCC to chemotherapy-induced apoptosis. Finally, targeting SATB2 or BRD7 effectively restricted the proliferation of YAP-high tumors in patient-derived xenografts and patient-derived organoids. Together, SATB2 is an oncogenic chromatin organizer in RCC, and targeting SATB2 is an effective strategy to suppress the YAP-high RCC.
A YAP-SATB2-NRF2 regulatory axis amplifies antioxidative stress signaling and provides potential therapeutic targets to enhance response to chemotherapy in renal cell carcinoma.
