Hypoxia-induced SATB homeobox 2 increases hypoxia-inducible factor-1-dependent tumorigenesis and drives bevacizumab resistance in lung adenocarcinoma.
6 affiliations
- 1Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou, 215006, China; Department of Medical Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Jiangsu, Suzhou, 215000, China.
- 2Department of Thoracic Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Jiangsu, Suzhou, 215000, China.
- 3Research Center for Experimental Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin Road II, Shanghai, 200025, China.
- 4Department of Medical Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Jiangsu, Suzhou, 215000, China.
- 5Department of Medical Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Jiangsu, Suzhou, 215000, China. Electronic address: [email protected].
- 6Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou, 215006, China. Electronic address: [email protected].
Abstract
Hypoxia-driven epigenetic remodeling is a critical determinant of lung adenocarcinoma (LUAD) progression and therapeutic resistance, yet the epigenetic mechanisms coordinating hypoxia signaling with tumor microenvironment remodeling remain incompletely understood. Here, by integrating LUAD cell models, murine tumor models, and spatial transcriptomics with reference-based cell-type deconvolution, we identify SATB2 as a previously unrecognized hypoxia-inducible epigenetic regulator in LUAD. HIF-1α, unlike HIF-2α, directly interacts with the promoter of SATB2, promoting its expression in hypoxic environments. Increased levels of SATB2 have been linked to more severe clinical and pathological characteristics as well as poorer outcomes for patients. Mechanistically, SATB2 physically interacts with HIF-1α and p300, while SATB2 loss reduces H3K27 acetylation and elongating RNA polymerase II occupancy at HIF-1 target loci, supporting a model in which SATB2 facilitates HIF-1α-dependent transcriptional elongation and establishes a positive feedback circuit that amplifies hypoxia-responsive transcriptional programs. Spatial transcriptomic analyses further show that SATB2-associated hypoxic programs are preferentially enriched within malignant tumor niches and are associated with remodeling of the local tumor microenvironment. Functionally, SATB2 promotes LUAD growth, metastasis, angiogenesis, and bevacizumab resistance in a HIF-1α-dependent manner, whereas genetic disruption of SATB2 or pharmacological inhibition of p300 enhances sensitivity to anti-angiogenic therapy. Collectively, these findings identify the SATB2-p300-HIF-1α axis as a hypoxia-responsive epigenetic regulatory mechanism linking transcriptional adaptation to malignant progression and resistance to anti-angiogenic therapy, and provide a preclinical rationale for further investigation of this pathway as a potential therapeutic vulnerability in LUAD.
Related
- Sequential colorectal cancer–based therapy including anti-angiogenics and 3rd-line trifluridine/tipiracil-bevacizumab for metastatic urachal adenocarcinoma: a case report
- ESM1 drives H4K8 lactylation to promote vasculogenic mimicry and bevacizumab resistance in ovarian cancer
- Inducible cysteine synthesis by CysK2 provides copper resistance in Mycobacterium tuberculosis
- Metabolic signature of phosphoethanolamine and arginine pathways predicts prognosis and immunotherapy resistance in lung adenocarcinoma
- A Human ABCG2 SNP Variant, P269S (rs34678167, c.805C>T), Increases Cellular Resistance to Mitoxantrone and SN-38 Without Detectable Differences in ABCG2 Abundance in Total and Biotinylated Protein Fractions
BibTeX
@article{ruan2026hypoxiainduced,
title = {{Hypoxia-induced SATB homeobox 2 increases hypoxia-inducible factor-1-dependent tumorigenesis and drives bevacizumab resistance in lung adenocarcinoma.}},
author = {Suhong Ruan and Tengteng Wei and Guangda Yuan and Yan Shen and Yangzi Li and Jing Ning and Feng Guo and Kai Chen},
journal = {Translational oncology},
year = {2026},
month = oct,
doi = {10.1016/j.tranon.2026.103069},
url = {https://europepmc.org/article/MED/42896440},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Hypoxia-induced SATB homeobox 2 increases hypoxia-inducible factor-1-dependent tumorigenesis and drives bevacizumab resistance in lung adenocarcinoma.
AU - Suhong Ruan
AU - Tengteng Wei
AU - Guangda Yuan
AU - Yan Shen
AU - Yangzi Li
AU - Jing Ning
AU - Feng Guo
AU - Kai Chen
PY - 2026
DA - 2026/10/19
JO - Translational oncology
DO - 10.1016/j.tranon.2026.103069
UR - https://europepmc.org/article/MED/42896440
AB - Hypoxia-driven epigenetic remodeling is a critical determinant of lung adenocarcinoma (LUAD) progression and therapeutic resistance, yet the epigenetic mechanisms coordinating hypoxia signaling with tumor microenvironment remodeling remain incompletely understood. Here, by integrating LUAD cell models, murine tumor models, and spatial transcriptomics with reference-based cell-type deconvolution, we identify SATB2 as a previously unrecognized hypoxia-inducible epigenetic regulator in LUAD. HIF-1α, unlike HIF-2α, directly interacts with the promoter of SATB2, promoting its expression in hypoxic environments. Increased levels of SATB2 have been linked to more severe clinical and pathological characteristics as well as poorer outcomes for patients. Mechanistically, SATB2 physically interacts with HIF-1α and p300, while SATB2 loss reduces H3K27 acetylation and elongating RNA polymerase II occupancy at HIF-1 target loci, supporting a model in which SATB2 facilitates HIF-1α-dependent transcriptional elongation and establishes a positive feedback circuit that amplifies hypoxia-responsive transcriptional programs. Spatial transcriptomic analyses further show that SATB2-associated hypoxic programs are preferentially enriched within malignant tumor niches and are associated with remodeling of the local tumor microenvironment. Functionally, SATB2 promotes LUAD growth, metastasis, angiogenesis, and bevacizumab resistance in a HIF-1α-dependent manner, whereas genetic disruption of SATB2 or pharmacological inhibition of p300 enhances sensitivity to anti-angiogenic therapy. Collectively, these findings identify the SATB2-p300-HIF-1α axis as a hypoxia-responsive epigenetic regulatory mechanism linking transcriptional adaptation to malignant progression and resistance to anti-angiogenic therapy, and provide a preclinical rationale for further investigation of this pathway as a potential therapeutic vulnerability in LUAD.
SN - 1936-5233
ER -