Anticancer Agents Med Chem. 2013 Jun; 13(5):762-7.

Inhibition of p53 acetylation by PCAF inhibitor anacardic acid derivative in BCR-ABL1-expressing cells.;  breaking resistance to DNA damage and possible therapeutical implications.  

Katarzyna Piwocka1, Frank J. Dekker 2.

1Laboratory of Cytometry, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;

2Department of Pharmaceutical Gene Modulation, University of Groningen, 9713 AV Groningen, The Netherlands.



Posttranslational modifications, including acetylation, are crucial regulators of many cellular processes, which participate in cancerogenesis, disease progression and resistance to therapy. Acetylation of non-histone proteins regulates gene expression, protein localization and activity, leading to significant changes in the signal transduction. Histone acetylotransferases (HATs) have been proposed as novel interesting drug targets. In this study we found that a small molecule anacardic acid derivative showing anti-HATs activity is able to induce cell death and sensitize apoptosis-resistant leukemia cells expressing BCR-ABL1 to DNA damage. Interestingly, CML cells showed higher sensitivity to PCAF inhibition. In the previous studies we showed that this inhibitor decreases acetylation of p53 at lysine 317/320 (K317/K320), which is the key event in the regulation of p53 translocation to the cytosol followed by Bax activation and induction of transcription-independent, p53-dependent apoptosis. Altogether, these findings provide direct evidence that PCAF-mediated acetylation of p53 was sufficient to protect leukemia cells from DNA damage-induced apoptosis and that this protection is diminished by treatment with a HAT inhibitor. Thus, we present a molecular mechanism that can be employed to develop HAT inhibitors further into a novel type of potential therapeutic agents to treat apoptosis-resistant leukemia.



Chronic myeloid leukemia cells expressing BCR-ABL1 are often characterized by resistance to classical apoptosis that is induced by DNA damage. Despite the application of imatinib and other new generation tyrosine kinase inhibitors (TKIs) in the clinic resistance to apoptosis in BCR-ABL1 expressing cells remains a significant challenge. Therefore, apoptosis resistance poses a substantial restriction to the  therapeutic strategies that can be employed in these types of cancer and novel therapeutic strategies are required.

The study by Kusio-Kobialka et al. focused on investigating whether a novel small molecule inhibitor of HATs will be able to induce cell death or sensitize apoptosis-resistant BCR-ABL1-expressing cells to DNA damage [1]. In our previous studies we showed that BCR-ABL1 increased PCAF level and acetylation of p53 protein at the lysine 317/320 residue. Treatment of BCR-ABL1 expressing cells with the DNA-damaging agent etoposide prevented translocation of p53 to the cytoplasm, protected from Bax activation and subsequent mitochondria-dependent apoptosis [2]. As acetylation of lysine 317/320 is regulated by PCAF, we verified the hypothesis that PCAF inhibitors will overcome resistance to apoptosis observed in BCR-ABL1-expressing cells.

Towards this aim we utilized anacardic acid (AA) derivative – MG153, which belongs to the family of AA derivatives. This derivative was designed and synthesized by us to optimize the HAT inhibitory potency of the natural product anacardic acid. Anacardic acid  was previously shown to  inhibit HATs such as PCAF and p300. We employed structure based design based on the crystal structure of the HATs PCAF and p300 and subsequently investigated this molecule in enzyme assays and cell-based studies [3].

We found that inhibition of PCAF by anacardic acid derivative MG153 decreased proliferation and induced apoptosis not only in parental 32D cells but also 32D cells expressing BCR-ABL1.  Moreover, CML cells showed higher sensitivity to HATs inhibition. Cell death correlated with a decrease of the mitochondrial membrane potential, classical DNA fragmentation and subG1 formation. Also, pretreatment with MG153 sensitized BCR-ABL1-expressing cells  to etoposide, a topoisomerase II inhibitor. This suggests that this compound can be used in a combined treatment together with classical DNA damaging drugs, commonly used in the clinic.

Our study presents a novel BCR-ABL1-dependent mechanism protecting from DNA-damage-induced cell death. We showed that increased acetylation of p53 at lysine 317/320 leads to inhibition of  transcription-independent proapoptotic functions of p53 and finally protection from cell death. It can, in addition to already known mechanisms, explain the resistance to p53-dependent apoptosis observed in CML cells expressing wt p53. We propose that the acetyltransferases regulating acetylation of p53 at lysine 317/320 are potent drug targets in CML cells. Our findings collectively indicate that small molecule HAT inhibitors – anacardic acid derivatives, are potent drugs for therapeutic intervention, which might be used in a single therapy or co-treatment to sensitize cells to DNA damage. Our data indicate that  further studies validating the clinical relevance of anacardic acid derivatives would be valuable.

Figure1 AA and MG153-2Fig. 1 – AA and MG132 structure

 Figure2 role of p53 acetylation in apoptosis-2

Fig. 2 – scheme of the p53 acetylation at lysine 317/320 and role in apoptosis



  1. Kusio-Kobialka M, Dudka-Ruszkowska W, Ghizzoni M, Dekker FJ, Piwocka K. 2013.  Inhibition of PCAF by anacardic acid derivative leads to apoptosis and breaks resistance to DNA damage in BCR-ABL-expressing cells. Anticancer Agents Med Chem. 13(5):762-7.
  2. Kusio-Kobialka M, Wolanin K, Podszywalow-Bartnicka P, Sikora E, Skowronek K, McKenna SL, Ghizzoni M, Dekker FJ, Piwocka K. 2012. Increased acetylation of lysine 317/320 of p53 caused by BCR-ABL protects from cytoplasmic translocation of p53 and mitochondria-dependent apoptosis in response to DNA damage. Apoptosis. 17(9):950-63.
  3. Ghizzoni M, Boltjes A, Graaf Cd, Haisma HJ, Dekker FJ. 2010. Improved inhibition of the histone acetyltransferase PCAF by an anacardic acid derivative. Bioorg Med Chem. 18(16):5826-34.


Acknowledgements: This study was supported by grants from the Ministry of Science and Higher Education in Poland 2P04A 05729 (to K.P.) and statutory funds from the Nencki Institute (to K.P.). K.P. is an ISAC Scholar. F.J.D is currently supported by a VIDI grant from theNetherlands organization of scientific research (NWO) and an ERC starting grant from the European Union.



Katarzyna Piwocka, PhD

Head of the Laboratory of Cytometry

Nencki Institute of Experimental Biology

Pasteur 3, Str

02-093 Warsaw



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