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A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer.

ABSTRACT: Sirtuin 2 (SIRT2) is an NAD(+)-dependent protein deacetylase whose targets include histone H4 lysine 16, p53, and ?-tubulin. Because deacetylation of p53 regulates its effect on apoptosis, pharmacological inhibition of SIRT2-dependent p53 deacetylation is of great therapeutic interest for the treatment of cancer. Here, we have identified two structurally related compounds, AEM1 and AEM2, which are selective inhibitors of SIRT2 (IC50 values of 18.5 and 3.8 ?M, respectively), but show only weak effects on other sirtuins such as SIRT1, SIRT3, and yeast Sir2. Interestingly, both compounds sensitized non-small cell lung cancer cell lines toward the induction of apoptosis by the DNA-damaging agent etoposide. Importantly, this sensitization was dependent on the presence of functional p53, thus establishing a link between SIRT2 inhibition by these compounds and p53 activation. Further, treatment with AEM1 and AEM2 led to elevated levels of p53 acetylation and to increased expression of CDKN1A, which encodes the cell cycle regulator p21(WAF1), as well as the pro-apoptotic genes PUMA and NOXA, three transcriptional targets of p53. Altogether, our data suggest that inhibition of SIRT2 by these compounds causes increased activation of p53 by decreasing SIRT2-dependent p53 deacetylation. These compounds thus provide a good opportunity for lead optimization and drug development to target p53-proficient cancers.

SUBMITTER: Hoffmann G

PROVIDER: S-EPMC3931077 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer.

Hoffmann Gesine G Breitenbücher Frank F Schuler Martin M Ehrenhofer-Murray Ann E AE

The Journal of biological chemistry 20131230 8

Sirtuin 2 (SIRT2) is an NAD(+)-dependent protein deacetylase whose targets include histone H4 lysine 16, p53, and α-tubulin. Because deacetylation of p53 regulates its effect on apoptosis, pharmacological inhibition of SIRT2-dependent p53 deacetylation is of great therapeutic interest for the treatment of cancer. Here, we have identified two structurally related compounds, AEM1 and AEM2, which are selective inhibitors of SIRT2 (IC50 values of 18.5 and 3.8 μM, respectively), but show only weak ef ...[more]

PMID: 24379401

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Project description:BackgroundLung cancer remains a leading cause of cancer death among both men and women in the United States. Treatment modalities available for this malignancy are inadequate and thus new drugs with improved pharmacological profiles and superior therapeutic indices are being continually explored. Noscapinoids constitute an emerging class of anticancer agents that bind tubulin but do not significantly alter the monomer/polymer ratio of tubulin. EM011, a rationally-designed member of this class of non-toxic agents, is more potent than the lead molecule, noscapine.ResultsHere we report that EM011 inhibited proliferation of a comprehensive panel of lung cancer cells with IC(50)'s ranging from 4-50 microM. In A549 human non-small cell lung cancer cells, the antiproliferative activity was mediated through blockage of cell-cycle progression by induction of a transient but robust mitotic arrest accompanied by activation of the spindle assembly checkpoint. The mitotically-arrested A549 cells then override the activated mitotic checkpoint and aberrantly exit mitosis without cytokinesis resulting in pseudo G1-like multinucleated cells that either succumb directly to apoptosis or continue another round of the cell-cycle. The accumulated enormous DNA perhaps acts as genotoxic stress to trigger cell death. EM011-induced apoptotic cell death in A549 cells was associated with a decrease of the Bcl2/BAX ratio, activation of caspase-3 and cleavage of PARP. Furthermore, EM011 induced downregulation of survivin expression over time of treatment. Abrogation of survivin led to an increase of cell death whereas, overexpression caused decreased apoptosis.ConclusionThese in vitro data suggest that EM011 mediates antiproliferative and proapoptotic activity in non-small cell A549 lung cancer cells by impeding cell-cycle progression and attenuating antiapoptotic signaling circuitries (viz. Bcl2, survivin). The study provides evidence for the potential usefulness of EM011 in chemotherapy of lung cancer.

Project description:BackgroundActivation of p53-mediated gene transcription is a critical cellular response to DNA damage and involves a phosphorylation-acetylation cascade of p53. The discovery of differences in the response to different agents raises the question whether some of the p53 oncosuppressor functions might be exerted by different posttranslational modifications. Stress-induced homeodomain-interacting protein kinase-2 (HIPK2) phosphorylates p53 at serine-46 (Ser46) for p53 apoptotic activity; p53 acetylation at different C-terminus lysines including p300-mediated lysine-382 (Lys382) is also required for full activation of p53 transcriptional activity. The purpose of the current study was to evaluate the interplay among HIPK2, p300, and p53 in p53 acetylation and apoptotic transcriptional activity in response to drug by using siRNA interference, p300 overexpression or deacetylase inhibitors, in cancer cells.ResultsKnockdown of HIPK2 inhibited both adriamycin-induced Ser46 phosphorylation and Lys382 acetylation in p53 protein; however, while combination of ADR and zinc restored Ser46 phosphorylation it did not recover Lys382 acetylation. Chromatin immunoprecipitation studies showed that HIPK2 was required in vivo for efficient p300/p53 co-recruitment onto apoptotic promoters and that both p53 modifications at Ser46 and Lys382 were necessary for p53 apoptotic transcription. Thus, p53Lys382 acetylation in HIPK2 knockdown as well as p53 apoptotic activity in response to drug could be rescued by p300 overexpression. Similar effect was obtained with the Sirt1-inhibitor nicotinamide. Interestingly trichostatin A (TSA), the inhibitor of histone deacetylase complexes (HDAC) did not have effect, suggesting that Sirt1 was the deacetylase involved in p53 deacetylation in HIPK2 knockdown.ConclusionThese results reveal a novel role for HIPK2 in activating p53 apoptotic transcription. Our results indicate that HIPK2 may regulate the balance between p53 acetylation and deacetylation, by stimulating on one hand co-recruitment of p300 and p53Lys382 on apoptotic promoters and on the other hand by inhibiting Sirt1 deacetylase activity. We attempted to reactivate p53 apoptotic transcriptional activity by rescuing both Ser46 and Lys382 modification in response to drug. Our data propose combination strategies for the treatment of tumors with dysfunctional p53 and/or HIPK2 that include classical chemotherapy with pharmacological or natural agents such as Sirt1-deacetylase inhibitors or zinc, respectively.

Dataset Information

A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer.

Publications

A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer.

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