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Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth.

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Title: Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth.
Authors: Stewart, Tracy Murray1 tmurray2@jhmi.edu, Foley, Jackson R.1, Holbert, Cassandra E.1, Klinke, Glynis2, Poschet, Gemot2, Steimbach, Raphael R.3,4, Miller, Aubry K.4,5, Casero Jr, Robert A.1 rcasero@jhmi.edu
Source: Journal of Biological Chemistry. Oct2022, Vol. 298 Issue 10, p1-9. 9p.
Subjects: Cell growth, Tumor growth, Spermidine, Cell proliferation, High throughput screening (Drug development)
Abstract: 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. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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PubTypeId: academicJournal
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  Data: Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth.
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  Data: <searchLink fieldCode="AR" term="%22Stewart%2C+Tracy+Murray%22">Stewart, Tracy Murray</searchLink><relatesTo>1</relatesTo><i> tmurray2@jhmi.edu</i><br /><searchLink fieldCode="AR" term="%22Foley%2C+Jackson+R%2E%22">Foley, Jackson R.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Holbert%2C+Cassandra+E%2E%22">Holbert, Cassandra E.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Klinke%2C+Glynis%22">Klinke, Glynis</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Poschet%2C+Gemot%22">Poschet, Gemot</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Steimbach%2C+Raphael+R%2E%22">Steimbach, Raphael R.</searchLink><relatesTo>3,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Miller%2C+Aubry+K%2E%22">Miller, Aubry K.</searchLink><relatesTo>4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Casero+Jr%2C+Robert+A%2E%22">Casero Jr, Robert A.</searchLink><relatesTo>1</relatesTo><i> rcasero@jhmi.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Oct2022, Vol. 298 Issue 10, p1-9. 9p.
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  Data: <searchLink fieldCode="DE" term="%22Cell+growth%22">Cell growth</searchLink><br /><searchLink fieldCode="DE" term="%22Tumor+growth%22">Tumor growth</searchLink><br /><searchLink fieldCode="DE" term="%22Spermidine%22">Spermidine</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+proliferation%22">Cell proliferation</searchLink><br /><searchLink fieldCode="DE" term="%22High+throughput+screening+%28Drug+development%29%22">High throughput screening (Drug development)</searchLink>
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  Data: 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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1016/j.jbc.2022.102407
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      – Code: eng
        Text: English
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        PageCount: 9
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    Subjects:
      – SubjectFull: Cell growth
        Type: general
      – SubjectFull: Tumor growth
        Type: general
      – SubjectFull: Spermidine
        Type: general
      – SubjectFull: Cell proliferation
        Type: general
      – SubjectFull: High throughput screening (Drug development)
        Type: general
    Titles:
      – TitleFull: Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth.
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            NameFull: Stewart, Tracy Murray
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            – D: 01
              M: 10
              Text: Oct2022
              Type: published
              Y: 2022
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              Value: 298
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