β-Hydroxybutyrate suppresses colorectal cancer.
β-Hydroxybutyrate suppresses colorectal cancer.
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DOI：
10.1038/s41586-022-04649-6
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发表时间：
2022-05
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
结直肠癌（CRC）是最常见的癌症之一，迫切需要新的预防和治疗策略。在这里，我们确定了一种代谢物信号通路，为实现这一目标提供了可行的见解。我们在CRC的本地动物模型中进行饮食筛选，发现生酮饮食表现出强烈的肿瘤抑制作用。酮体β-羟基丁酸酯（BHB）重现了生酮饮食的这些特性，可减少结肠隐窝细胞的增殖并有效抑制肠道肿瘤生长。我们发现BHB通过表面受体Hcar 2起作用并诱导转录调节因子Hopx，从而改变基因表达并抑制细胞增殖。来自CRC患者的活检组织的癌症类器官测定和单细胞RNA测序提供了证据，表明BHB水平升高和活性HOPX与人类肠上皮细胞增殖减少相关。因此，这项研究确定了一个BHB触发的途径调节肠道肿瘤的发生，并表明口服或全身干预与单一的代谢物可以补充目前的预防和治疗策略CRC。
Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
DOI：
10.1126/science.1227166
发表时间：
2013-01-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shimazu T;Hirschey MD;Newman J;He W;Shirakawa K;Le Moan N;Grueter CA;Lim H;Saunders LR;Stevens RD;Newgard CB;Farese RV Jr;de Cabo R;Ulrich S;Akassoglou K;Verdin E
通讯作者：
Verdin E
影响因子：
64.5
作者：
Kaiko GE;Ryu SH;Koues OI;Collins PL;Solnica-Krezel L;Pearce EJ;Pearce EL;Oltz EM;Stappenbeck TS
通讯作者：
Stappenbeck TS
影响因子：
64.5
作者：
Ang, Qi Yan;Alexander, Margaret;Turnbaugh, Peter J.
通讯作者：
Turnbaugh, Peter J.
影响因子：
--
作者：
Soneson C;Love MI;Robinson MD
通讯作者：
Robinson MD