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Abstract
There are limited therapeutic options for patients with advanced prostate cancer (PCa). We previously found that heat shock factor 1 (HSF1) expression is increased in PCa and is an actionable target. In this manuscript, we identify that HSF1 regulates the conversion of homocysteine to cystathionine in the transsulfuration pathway by altering levels of cystathionine-β-synthase (CBS). We find that HSF1 directly binds the CBS gene and upregulates CBS mRNA levels. Targeting CBS decreases PCa growth and induces tumor cell death while benign prostate cells are largely unaffected. Combined inhibition of HSF1 and CBS results in more pronounced inhibition of PCa cell proliferation and reduction of transsulfuration pathway metabolites. Combination of HSF1 and CBS knockout decreases tumor size for a small cell PCa xenograft mouse model. Our study thus provides new insights into the molecular mechanism of HSF1 function and an effective therapeutic strategy against advanced PCa.
HSF1 regulates the conversion of homocysteine to cystathionine in the trans-sulfuration pathway by altering levels of cystathionine-β-synthase (CBS), and targeting CBS decreases pancreatic cancer growth while leaving benign prostate cells largely unaffected.
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1 Duke University School of Medicine, Room 301M, Duke South DUMC 3712, Department of Pathology and Duke Cancer Institute, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961)
2 College of Basic Medical Sciences, and the First Hospital of China Medical University, Department of Pathology, Shenyang, China (GRID:grid.412636.4)
3 First Affiliated Hospital of Anhui Medical University, Urology Department, Hefei, China (GRID:grid.412679.f) (ISNI:0000 0004 1771 3402)
4 Baylor College of Medicine, 1100 Bates Ave One Baylor Plaza, Children’s Nutrition Research Center, Department of Pediatrics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X)
5 Baylor College of Medicine, 1100 Bates Ave One Baylor Plaza, Children’s Nutrition Research Center, Department of Pediatrics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); 1100 Bates Ave Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X)