Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth.
Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth.
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DOI：
10.1016/j.jbc.2022.102407
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发表时间：
2022-10
影响因子：
4.8
通讯作者：
Casero Jr, Robert A.
中科院分区：
文献类型：
--
作者：
Stewart, Tracy Murray;Foley, Jackson R.;Holbert, Cassandra E.;Klinke, Glynis;Poschet, Gernot;Steimbach, Raphael R.;Miller, Aubry K.;Casero Jr, Robert A.
细胞溶质组蛋白脱乙酰基酶-10（HDAC 10）特异性地使修饰的多胺N8-乙酰亚精胺（N8-AcSpd）脱乙酰基。虽然N8-AcSpd的细胞内浓度低，但细胞外来源可能丰富，特别是在结肠腔中。细胞外多胺，包括来自饮食和微生物群的多胺，可以支持局部和远处的肿瘤生长。然而，N8-AcSpd在这种情况下的贡献是未知的。我们假设HDAC 10通过将N8- AcSpd转化为亚精胺，可以在多胺生物合成减少的情况下提供这种生长支持多胺的来源，例如在多胺靶向抗癌疗法中。多胺生物合成的抑制剂，包括α-二氟甲基鸟氨酸（DFMO），抑制肿瘤生长，但细胞外多胺的代偿性摄取限制了其临床成功。将DFMO与多胺摄取抑制剂组合改善了抗肿瘤反应。然而，乙酰化多胺可能使用不同的运输机制比母体分子。在这里，我们使用CRISPR/Cas9介导的HDAC 10敲除细胞系和HDAC 10特异性抑制剂来研究HDAC 10在维持肿瘤细胞增殖中的作用。我们证明了DFMO相关的多胺耗竭对细胞生长的抑制作用被外源性N8-AcSpd（生理浓度）成功拯救，该物质仅在具有HDAC 10活性的细胞系中转化为亚精胺和精胺。此外，我们发现HDAC 10的丢失阻止了多胺水平的恢复和生长拯救，暗示HDAC 10支持多胺相关的肿瘤生长。这些数据表明HDAC 10特异性抑制剂作为一种抗肿瘤策略的效用，可能在改善对多胺阻断疗法的反应方面具有价值。此外，本研究中开发的基于细胞的检测方法提供了一种筛选潜在选择性HDAC 10抑制剂的廉价、高通量方法。
Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd). Although intracellular concentrations of N8-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor growth both locally and at distant sites. However, the contribution of N8-AcSpd in this context is unknown. We hypothesized that HDAC10, by converting N8- AcSpd to spermidine, may provide a source of this growth-supporting polyamine in circumstances of reduced polyamine biosynthesis, such as in polyamine-targeting anticancer therapies. Inhibitors of polyamine biosynthesis, including α-difluoromethylornithine (DFMO), inhibit tumor growth, but compensatory uptake of extracellular polyamines has limited their clinical success. Combining DFMO with inhibitors of polyamine uptake have improved the antitumor response. However, acetylated polyamines may use different transport machinery than the parent molecules. Here, we use CRISPR/Cas9-mediated HDAC10-knockout cell lines and HDAC10-specific inhibitors to investigate the contribution of HDAC10 in maintaining tumor cell proliferation. We demonstrate inhibition of cell growth by DFMO-associated polyamine depletion is successfully rescued by exogenous N8-AcSpd (at physiological concentrations), which is converted to spermidine and spermine, only in cell lines with HDAC10 activity. Furthermore, we show loss of HDAC10 prevents both restoration of polyamine levels and growth rescue, implicating HDAC10 in supporting polyamine-associated tumor growth. These data suggest the utility of HDAC10-specific inhibitors as an antitumor strategy that may have value in improving the response to polyamine-blocking therapies. Additionally, the cell-based assay developed in this study provides an inexpensive, high-throughput method of screening potentially selective HDAC10 inhibitors.
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DOI：
10.3390/medsci10020031
发表时间：
2022-06-10
期刊：
Medical sciences (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.9
作者：
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通讯作者：
Altomare, Deborah A.
DOI：
10.1016/s0378-4347(00)83621-x
发表时间：
1986-07-11
期刊：
JOURNAL OF CHROMATOGRAPHY
影响因子：
--
作者：
KABRA, PM;LEE, HK;MARTON, LJ
通讯作者：
MARTON, LJ
影响因子：
16.6
作者：
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通讯作者：
Globisch, Daniel
影响因子：
3.9
作者：
BLANKENSHIP, J;WALLE, T
通讯作者：
WALLE, T