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Gene Review

SAT1  -  spermidine/spermine N1-acetyltransferase 1

Homo sapiens

Synonyms: DC21, Diamine acetyltransferase 1, KFSD, KFSDX, Polyamine N-acetyltransferase 1, ...
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Disease relevance of SAT1

  • These data suggested that SSAT and SMO(PAOh1) activities are the major mediators of the cellular response of breast tumor cells to BENSpm and that PAO plays little or no role in this response [1].
  • Similar to previous observations with SSAT expression, PAOh1/SMO induction was found to occur primarily in non-small-cell lung cancers cell lines [2].
  • The observation that apple procyanidins enhance polyamine catabolism and reduce polyamine biosynthesis activity similar to known inducers of SSAT, without sharing their toxicity, and the potentiation of these effects by low concentrations of MDL 72527 suggests apple procyanidins for chemopreventive and therapeutic interventions [3].
  • Therefore, pharmacological activation of PPARgamma and/or induction of SSAT may represent a therapeutic or preventive strategy for treating colorectal cancer [4].
  • Based on our findings, p38 MAPK and transcription factor PPARgamma can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity, respectively, in a cell culture model of colon cancer [5].

High impact information on SAT1

  • We conclude that SSAT directly binds to the alpha9 cytoplasmic domain and mediates alpha9-dependent enhancement of cell migration, presumably by localized effects on acetylation of polyamines or of unidentified substrates [6].
  • The spermine/spermidine N(1)-acetyltransferase gene (SSAT) was successfully validated by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses [7].
  • Implication of SSAT by gene expression and genetic variation in suicide and major depression [7].
  • A variant located in the SSAT polyamine-responsive element regulatory region (SSAT342A/C) demonstrated a significant effect of genotype on SSAT brain expression levels (F(1) = 5.34; P = .02) [7].
  • We have expressed human SSAT from the cloned cDNA in Escherichia coli and have determined high-resolution structures of wild-type and mutant SSAT, as the free dimer and in binary and ternary complexes with CoA, acetyl-CoA (AcCoA), spermine, and the inhibitor N1,N11bis-(ethyl)-norspermine (BE-3-3-3) [8].

Chemical compound and disease context of SAT1

  • The limited induction of spermidine/spermine N1-acetyltransferase (SSAT) activity has been implicated as an important determinant of the reduced response to the spermine analogue N1,N12-bis(ethyl)spermine (BESpm) by the cisplatin or cis-diamminedichloroplatinum(II) (cDDP)-resistant human ovarian carcinoma cell line (C13*) [9].
  • Extreme inducibility of spermidine/spermine acetyltransferase (SSAT) by bis-ethyl derivatives of spermine in human large cell lung carcinoma and melanoma cells has prompted biochemical characterization of the purified enzyme [10].
  • The link between SSAT activity and cellular toxicity is thought to be based on the production of H(2)O(2) by the activity of the constitutive APAO that uses the SSAT-produced acetylated polyamines [11].
  • In MALME-3M human melanoma cells the polyamine analog N1,N12-bis(ethyl)spermine (BESPM) suppresses the key polyamine biosynthetic enzymes, ornithine and S-adenosylmethionine decarboxylase, and increases the polyamine catabolizing enzyme, spermidine/spermine N1-acetyl-transferase (SSAT) by more than 200-fold [12].
  • We recently reported that the combination of N(1), N(11)-diethylnorspermine (DENSPM) and 5-fluorouracil (5-FU) synergistically induces SSAT expression, depletes polyamine levels and causes apoptosis in colon cancer cells [13].

Biological context of SAT1

  • Analysis of mRNA levels in cell lines and ESTs (expressed sequence tags) from various tissues by digiNorthern (a web-based tool for virtually displaying expression profiles of query genes based on EST sequences) indicated that SSAT-1 tends to be more widely and highly expressed than SSAT-2 [14].
  • Cytosolic spermidine/spermine acetyltransferase (SSAT) catalyzes the acetylation of the N(1)-propylamino groups of spermine and spermidine [15].
  • Moreover, both phosphorylation processes are involved in the uptake of SSAT into rat liver mitochondria [15].
  • A significant and positive correlation between PPARgamma and the SSAT gene expression was observed in both normal and neoplastic tissue (r = 0.73, p < 0.0001; r = 0.65, p < 0.0001, respectively) [4].
  • CONCLUSION: In conclusion, our data demonstrated a close relationship between PPARgamma and SSAT in human colorectal cancer and this could represent an attempt to decrease polyamine levels and to reduce cell growth and tumour development [4].

Anatomical context of SAT1

  • BENSpm differentially induced SSAT and SMO(PAOh1) mRNA and activity in several breast cancer cell lines, whereas no N1-acetylpolyamine oxidase PAO mRNA or activity was detected [1].
  • RESULTS: PPARgamma expression, as well as SSAT and ODC mRNA levels were significantly higher in cancer as compared to normal mucosa [4].
  • PPRE-2, at +48 bases relative to the transcription start site, is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPAR gamma in the Caco-2 cells as shown by transfection and gel shift experiments [16].
  • This led us to the identification of two peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) in the SSAT gene [16].
  • Overexpression of SSAT caused rounding and loss of cell anchorage and significantly altered the morphology of actin-containing filopodia, suggesting an adhesion defect [17].

Associations of SAT1 with chemical compounds

  • When transiently transfected into HEK-293 cells, SSAT-1 decreased spermidine and spermine pools by approximately 30%, while, at the same time, significantly increasing putrescine, N (1)-acetylspermidine, N (1)-acetylspermine and N (1), N (12)-diacetylspermine pools [14].
  • Spermine/spermidine acetyltransferase (SSAT) activity was determined by a radiochemical assay [5].
  • The clinically relevant polyamine analogue N(1),N(11)-diethylnorspermine (DENSPM) inhibits cell growth by down-regulating polyamine biosynthesis, up-regulating polyamine catabolism at the level of spermidine/spermine N(1)-acetyltransferase (SSAT), and depleting intracellular polyamine pools [18].
  • In contrast to Caco-2-wild type cells (P < 0.05), resveratrol failed to increase SSAT activity in dominant-negative PPARgamma cells [5].
  • Dose-dependent inhibition of polyamine oxidase, an enzyme that oxidizes acetylated polyamines generated by SSAT and releases toxic by-products such as H(2)O(2) and aldehydes, prevented cytochrome c release, caspase activation, and apoptosis [19].

Enzymatic interactions of SAT1

  • The present work evaluates the ability of the cAMP-independent Ser/Thr-protein kinase CK1 to phosphorylate SSAT [15].
  • Casein kinase 2 purified from human erythrocyte cytosol has been found to phosphorylate human spermidine/spermine N1-acetyltransferase (SSAT) expressed as a fusion protein in E. coli and purified to homogeneity with a specific activity similar to that reported for pure human SSAT [20].

Other interactions of SAT1

  • ODC and SSAT activity were measured by a radiometric technique [4].
  • Mathematical/Statistical modeling of the data from time-course and concentration-effect experiments of gene expression from nine polyamine pathway genes represented on the HGU95Av2 chip, indicates that three biosynthetic pathway genes (SAMDC, ODC1 and SRM) are down-regulated and one catabolic pathway gene (SSAT) is up-regulated [21].
  • The kcat/K(m) values for spermine and spermidine for SSAT2 were <0.0003% those of SSAT1 [22].
  • In contrast, the coaddition of catalase or PAO inhibitor has no effect on reducing HMW DNA fragmentation induced by N1-ethyl-N11-[(cycloheptyl)methyl]-4,8,-diazaundecane, which does not induce SSAT and does not deplete intracellular polyamines [23].

Analytical, diagnostic and therapeutic context of SAT1

  • METHODS: PPARgamma, ODC and SSAT mRNA levels were evaluated by reverse transcriptase and real-time PCR [4].
  • Additionally, since clinical trials have begun on one of the SSAT-inducing polyamine analogues, this antiserum may be useful as a diagnostic tool in differentiating responsive and nonresponsive tumor cell populations in treated patients [24].
  • Northern blots confirmed increased SSAT RNA levels in these colon cancer cells [16].
  • To test this, the responses of the polyamine catabolic enzymes spermidine/spermine acetyltransferase (SSAT) and polyamine oxidase (PAO) were determined using a new high-performance liquid chromatography assay to measure the products of these enzymes [25].
  • Among the up-regulated clones the RT-PCR and Northern analyses revealed an unusual transcript of the spermidine/spermine N1-acetyltransferase (SSAT) gene that was shown to be an alternatively spliced form containing an additional 110-bp exon [26].


  1. Spermine oxidase SMO(PAOh1), Not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated human breast cancer cell lines. Pledgie, A., Huang, Y., Hacker, A., Zhang, Z., Woster, P.M., Davidson, N.E., Casero, R.A. J. Biol. Chem. (2005) [Pubmed]
  2. Induction of the PAOh1/SMO polyamine oxidase by polyamine analogues in human lung carcinoma cells. Devereux, W., Wang, Y., Stewart, T.M., Hacker, A., Smith, R., Frydman, B., Valasinas, A.L., Reddy, V.K., Marton, L.J., Ward, T.D., Woster, P.M., Casero, R.A. Cancer Chemother. Pharmacol. (2003) [Pubmed]
  3. Potentiation of apple procyanidin-triggered apoptosis by the polyamine oxidase inactivator MDL 72527 in human colon cancer-derived metastatic cells. Gossé, F., Roussi, S., Guyot, S., Schoenfelder, A., Mann, A., Bergerat, J.P., Seiler, N., Raul, F. Int. J. Oncol. (2006) [Pubmed]
  4. Peroxisome proliferator-activated receptor gamma and spermidine/spermine N1-acetyltransferase gene expressions are significantly correlated in human colorectal cancer. Linsalata, M., Giannini, R., Notarnicola, M., Cavallini, A. BMC Cancer (2006) [Pubmed]
  5. Peroxisome proliferator-activated receptor gamma as a molecular target of resveratrol-induced modulation of polyamine metabolism. Ulrich, S., Loitsch, S.M., Rau, O., von Knethen, A., Brüne, B., Schubert-Zsilavecz, M., Stein, J.M. Cancer Res. (2006) [Pubmed]
  6. Spermidine/spermine N1-acetyltransferase specifically binds to the integrin alpha9 subunit cytoplasmic domain and enhances cell migration. Chen, C., Young, B.A., Coleman, C.S., Pegg, A.E., Sheppard, D. J. Cell Biol. (2004) [Pubmed]
  7. Implication of SSAT by gene expression and genetic variation in suicide and major depression. Sequeira, A., Gwadry, F.G., Ffrench-Mullen, J.M., Canetti, L., Gingras, Y., Casero, R.A., Rouleau, G., Benkelfat, C., Turecki, G. Arch. Gen. Psychiatry (2006) [Pubmed]
  8. Structures of wild-type and mutant human spermidine/spermine N1-acetyltransferase, a potential therapeutic drug target. Bewley, M.C., Graziano, V., Jiang, J., Matz, E., Studier, F.W., Pegg, A.E., Coleman, C.S., Flanagan, J.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Spermidine/spermine N1-acetyltransferase transient overexpression restores sensitivity of resistant human ovarian cancer cells to N1,N12-bis(ethyl)spermine and to cisplatin. Marverti, G., Giuseppina Monti, M., Pegg, A.E., McCloskey, D.E., Bettuzzi, S., Ligabue, A., Caporali, A., D'Arca, D., Moruzzi, M.S. Carcinogenesis (2005) [Pubmed]
  10. Characterization of human spermidine/spermine N1-acetyltransferase purified from cultured melanoma cells. Libby, P.R., Ganis, B., Bergeron, R.J., Porter, C.W. Arch. Biochem. Biophys. (1991) [Pubmed]
  11. The role of polyamine catabolism in anti-tumour drug response. Casero, R.A., Wang, Y., Stewart, T.M., Devereux, W., Hacker, A., Wang, Y., Smith, R., Woster, P.M. Biochem. Soc. Trans. (2003) [Pubmed]
  12. Polyamine and polyamine analog regulation of spermidine/spermine N1-acetyltransferase in MALME-3M human melanoma cells. Fogel-Petrovic, M., Shappell, N.W., Bergeron, R.J., Porter, C.W. J. Biol. Chem. (1993) [Pubmed]
  13. Inactivation of IkappaB contributes to transcriptional activation of spermidine/spermine N(1)-acetyltransferase. Choi, W., Proctor, L., Xia, Q., Feng, Y., Gerner, E.W., Chiao, P.J., Hamilton, S.R., Zhang, W. Mol. Carcinog. (2006) [Pubmed]
  14. Genomic identification and biochemical characterization of a second spermidine/spermine N1-acetyltransferase. Chen, Y., Vujcic, S., Liang, P., Diegelman, P., Kramer, D.L., Porter, C.W. Biochem. J. (2003) [Pubmed]
  15. Phosphorylation of recombinant human spermidine/spermine N(1)-acetyltransferase by CK1 and modulation of its binding to mitochondria: a comparison with CK2. Bordin, L., Vargiu, C., Clari, G., Brunati, A.M., Colombatto, S., Salvi, M., Grillo, M.A., Toninello, A. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  16. Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. Babbar, N., Ignatenko, N.A., Casero, R.A., Gerner, E.W. J. Biol. Chem. (2003) [Pubmed]
  17. Overexpression of SSAT in kidney cells recapitulates various phenotypic aspects of kidney ischemia-reperfusion injury. Wang, Z., Zahedi, K., Barone, S., Tehrani, K., Rabb, H., Matlin, K., Casero, R.A., Soleimani, M. J. Am. Soc. Nephrol. (2004) [Pubmed]
  18. The role of mitogen-activated protein kinase activation in determining cellular outcomes in polyamine analogue-treated human melanoma cells. Chen, Y., Alm, K., Vujcic, S., Kramer, D.L., Kee, K., Diegelman, P., Porter, C.W. Cancer Res. (2003) [Pubmed]
  19. Apoptotic signaling in polyamine analogue-treated SK-MEL-28 human melanoma cells. Chen, Y., Kramer, D.L., Diegelman, P., Vujcic, S., Porter, C.W. Cancer Res. (2001) [Pubmed]
  20. Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. Bordin, L., Vargiu, C., Colombatto, S., Clari, G., Testore, G., Toninello, A., Grillo, M.A. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  21. Platinum drug effects on the expression of genes in the polyamine pathway: time-course and concentration-effect analysis based on Affymetrix gene expression profiling of A2780 ovarian carcinoma cells. Varma, R., Hector, S., Greco, W.R., Clark, K., Hawthorn, L., Porter, C., Pendyala, L. Cancer Chemother. Pharmacol. (2007) [Pubmed]
  22. Spermidine/spermine-N1-acetyltransferase-2 (SSAT2) acetylates thialysine and is not involved in polyamine metabolism. Coleman, C.S., Stanley, B.A., Jones, A.D., Pegg, A.E. Biochem. J. (2004) [Pubmed]
  23. The role of polyamine catabolism in polyamine analogue-induced programmed cell death. Ha, H.C., Woster, P.M., Yager, J.D., Casero, R.A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  24. Immunohistochemical staining of human spermidine/spermine N1-acetyltransferase superinduced in response to treatment with antitumor polyamine analogues. Casero, R.A., Gabrielson, E.W., Pegg, A.E. Cancer Res. (1994) [Pubmed]
  25. Pneumocystis carinii polyamine catabolism. Merali, S. J. Biol. Chem. (1999) [Pubmed]
  26. Induction of alternatively spliced spermidine/spermine N1-acetyltransferase mRNA in the human kidney cells infected by venezuelan equine encephalitis and tick-borne encephalitis viruses. Nikiforova, N.N., Velikodvorskaja, T.V., Kachko, A.V., Nikolaev, L.G., Monastyrskaya, G.S., Lukyanov, S.A., Konovalova, S.N., Protopopova, E.V., Svyatchenko, V.A., Kiselev, N.N., Loktev, V.B., Sverdlov, E.D. Virology (2002) [Pubmed]
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