SETD2 loss in renal epithelial cells drives epithelial-to-mesenchymal transition in a TGF-β-independent manner.

Autor: Wang T; Molecular Pharmacology and Experimental Therapeutics Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Wagner RT; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Hlady RA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Pan X; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Zhao X; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Kim S; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Wang L; Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA., Lee JH; Epigenomics Development Laboratory, Mayo Clinic, Rochester, MN, USA.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Luo H; Division of Hematology and Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA., Castle EP; Department of Urology, Tulane University, New Orleans, LA, USA., Lake DF; School of Life Sciences, Arizona State University, Tempe, AZ, USA., Ho TH; Division of Hematology and Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA., Robertson KD; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2024 Jan; Vol. 18 (1), pp. 44-61. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1002/1878-0261.13487
Abstrakt: Histone-lysine N-methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial-to-mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion, and stemness in a transforming growth factor-beta-independent manner. This newly identified EMT program is triggered in part through secreted factors, including cytokines and growth factors, and through transcriptional reprogramming. RNA-seq and assay for transposase-accessible chromatin sequencing uncovered key transcription factors upregulated upon SETD2 loss, including SOX2, POU2F2 (OCT2), and PRRX1, that could individually drive EMT and stemness phenotypes in SETD2 wild-type (WT) cells. Public expression data from SETD2 WT/mutant ccRCC support the EMT transcriptional signatures derived from cell line models. In summary, our studies reveal that SETD2 is a key regulator of EMT phenotypes through cell-intrinsic and cell-extrinsic mechanisms that help explain the association between SETD2 loss and ccRCC metastasis.
(© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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