Heat shock factor 1 directly regulates transsulfuration pathway to promote prostate cancer proliferation and survival

Authors: HAUCK, J. SPENCER - Duke University; MOON, DAVID - Duke University; JIANG, XUE - Duke University; WANG, MU-EN - Duke University; ZHAO, YUE - Jilin University; XU, LINGFAN - Anhui University Of Chinese Medicine; QUANG, HOLLY - Children'S Nutrition Research Center (CNRC); BUTLER, WILLIAM - Duke University; CHEN, MING - Duke University; MACIAS, EVERARDO - Duke University; GAO, XIA - Children'S Nutrition Research Center (CNRC); HE, YIPING - Duke University; HUANG, JIAOTI - Duke University

Submitted to: Communications Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/19/2023
Publication Date: 1/3/2024
Citation: Hauck, J., Moon, D., Jiang, X., Wang, M., Zhao, Y., Xu, L., Quang, H., Butler, W., Chen, M., Macias, E., Gao, X., He, Y., Huang, J. 2024. Heat shock factor 1 directly regulates transsulfuration pathway to promote prostate cancer proliferation and survival. Communications Biology. 7:Article 9. https://doi.org/10.1038/s42003-023-05727-9.
DOI: https://doi.org/10.1038/s42003-023-05727-9

Interpretive Summary: There are limited therapeutic options for patients with advanced prostate cancer (PCa). Here we found that heat shock factor 1 (HSF1) regulates the conversion of homocysteine to cystathionine in the transsulfuration pathway by altering levels of cystathionine-B-synthase (CBS). 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 tumor growht in 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.

Technical 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-B-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.