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.

中文翻译：

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以SIRT1为中心的电路可调节乳腺癌的干性和转移。

癌症干细胞（CSC）指导的肿瘤内异质性是乳腺癌耐药性和远处转移的主要原因。在这里，我们确定了SIRT1-PRRX1-KLF4-ALDH1电路，该电路耦合了CSC，耐化学性，转移和老化。长寿蛋白SIRT1使乙酰上皮-间质转化（EMT）诱导剂PRRX1脱乙酰化并使其稳定，从而抑制核心干因子KLF4的转录。SIRT1的丢失使PRRX1不稳定，抑制KLF4，并激活ALDH1的转录，后者诱导CSCs并在功能上标记CSC，从而导致耐药性和转移性复发。在临床上，PRRX1的水平与SIRT1正相关，而KLF4则呈反相关。重要的，KLF4抑制剂Kenpaullone使乳腺癌细胞和异种移植肿瘤对紫杉醇敏感并改善治疗效果。我们的发现描绘了一个以SIRT1为中心的电路，该电路调节CSC的起源，并且靶向该途径可能是一种有前途的治疗策略。