A SIRT1-centered circuitry regulates breast cancer stemness and metastasis.

Abstract	Cancer stem cell (CSC)-dictated intratumor heterogeneity accounts for the majority of drug-resistance and distant metastases of breast cancers. Here, we identify a SIRT1-PRRX1-KLF4-ALDH1 circuitry, which couples CSCs, chemo-resistance, metastasis and aging. Pro-longevity protein SIRT1 deacetylates and stabilizes the epithelial-to-mesenchymal-transition (EMT) inducer PRRX1, which inhibits the transcription of core stemness factor KLF4. Loss of SIRT1 destabilizes PRRX1, disinhibits KLF4, and activates the transcription of ALDH1, which induces and functionally marks CSCs, resulting in chemo-resistance and metastatic relapse. Clinically, the level of PRRX1 is positively linked to SIRT1, whereas KLF4 is reversely correlated. Importantly, KLF4 inhibitor Kenpaullone sensitizes breast cancer cells and xenograft tumors to Paclitaxel and improves therapeutic effects. Our findings delineate a SIRT1-centered circuitry that regulates CSC origination, and targeting this pathway might be a promising therapeutic strategy.
Authors	Lei Shi, Xiaolong Tang, Minxian Qian, Zuojun Liu, Fanbiao Meng, Li Fu, Zimei Wang, Wei-Guo Zhu, Jian-Dong Huang, Zhongjun Zhou, Baohua Liu
Journal	Oncogene (Oncogene) Vol. 37 Issue 49 Pg. 6299-6315 (12 2018) ISSN: 1476-5594 [Electronic] England
PMID	30038266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Homeodomain Proteins Isoenzymes KLF4 protein, human Klf4 protein, mouse Kruppel-Like Factor 4 Kruppel-Like Transcription Factors PRRX1 protein, human Aldehyde Dehydrogenase 1 Family ALDH1A1 protein, human ALDH1A1 protein, mouse Retinal Dehydrogenase SIRT1 protein, human Sirtuin 1
Topics	Aging (genetics, metabolism, pathology) Aldehyde Dehydrogenase 1 Family Animals Breast Neoplasms (metabolism, pathology) Cell Line, Tumor Drug Resistance, Neoplasm (physiology) Female Gene Expression Regulation, Neoplastic (physiology) Homeodomain Proteins (metabolism) Humans Isoenzymes (metabolism) Kruppel-Like Factor 4 Kruppel-Like Transcription Factors (metabolism) Mice Mice, Nude Neoplasm Invasiveness (genetics, pathology) Neoplastic Stem Cells (metabolism, pathology) Retinal Dehydrogenase (metabolism) Signal Transduction (physiology) Sirtuin 1 (metabolism) Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!