The therapeutic potential of targeting HDAC6 with Tubastatin A in TFK-1 and EGI-1 cholangiocarcinoma cells

The therapeutic potential of targeting HDAC6 with Tubastatin A in TFK-1 and EGI-1 cholangiocarcinoma cells

Cholangiocarcinoma (CCA) is a highly aggressive and invasive malignancy with a poor diagnosis because of the resistance, relapse and limited therapy. Histone deacetylases (HDAC) are a class of enzyme that have important roles in epigenetic modulations. These enzymes are intensely studied and HDAC inhibitors are considered as potent anticancer agents in both solid tumors and hematological malignancies. HDAC inhibitors can affect and induce different mechanisms such as cell cycle arrest, differentiation, and cell death. In this study, we aim to investigate the cytotoxic effect of Tubastatin A, which is a selective HDAC6 inhibitor, on cholangiocarcinoma cell lines, TFK-1 and EGI-1, by MTT assay. Besides, it was aimed to examine the impact on colony formation potential of the cells. The effect of the inhibitor on cell cycle distribution was also examined by using flow cytometry. Tubastatin A has significantly decreased the colony formation and changed cell cycle progression. Taken together, our results suggest that Tubastatin A could be a potent inhibitor against cholangiocarcinoma. On the basis of these results, further mechanistic studies are required to elucidate the antineoplastic activity of Tubastatin A.

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  • [1] Pant K., Peixoto E., Richard S. Gradilone, S. A., Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma, Cells, 9(3) (2020) 780.
  • [2] Rizvi S., Gores G. J., Pathogenesis, diagnosis, and management of cholangiocarcinoma, Gastroenterology, 145(6) (2013) 1215-29.
  • [3] Dawson M. A., Kouzarides T., Cancer epigenetics: From mechanism to therapy, Cell, 150(1) (2012) 12-27.
  • [4] Weinhold B., Epigenetics: the science of change, Environ. Health Perspect., 114(3) (2006) 160-7.
  • [5] Li Y., Seto E., HDACs and HDAC inhibitors in cancer development and therapy, Cold Spring Harb. Perspect. Med., 6(10) (2016) a026831.
  • [6] Sriraks R., Limpaiboon T., Histone deacetylases and their inhibitors as potential therapeutic drugs for cholangiocarcinoma–cell line findings, Asian Pacific J. Cancer Prev., 14(4) (2013) 2503-2508.
  • [7] Dokmanovic M., Clarke C., Marks P. A., Histone deacetylase inhibitors: Overview and perspectives, Molecular Cancer Research, 5(10) (2007) 981-989.
  • [8] Hubbert C., Guardiola A., Shao R., Kawaguchi Y., Ito A., Nixon A., Yoshida M., Wang X. F., Yao T. P., HDAC6 is a microtubuleassociated deacetylase, Nature, 417(6887) (2002) 455-458.
  • [9] Sakamoto K. M., Aldana-Masangkay G. I., The role of HDAC6 in cancer, Journal of Biomedicine and Biotechnology, 2011 (2011) 875824.
  • [10] Gradilone S. A., Pisarello M. J., LaRusso N. F., Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma, Curr. Drug Targets, 18(8) (2015) 958-963.
  • [11] Gradilone S. A., Radtke B. N., Bogert P. S., Huang B. Q., Gajdos G. B., LaRusso N. F., HDAC6 inhibition restores ciliary expression and decreases tumor growth, Cancer Res., 73(7) (2013) 2259-2270.
  • [12] Gradilone S. A., Gradilone S. A., Habringer S., Masyuk T. V., Howard B. N., Masyuk A. I., Larusso N. F., HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis, Am. J. Pathol, 184(3) (2014) 600– 608.
  • [13] Urdiciain A., Erausquin E., Meléndez B., Rey J. A., Idoate M. A., Castresana J. S., Tubastatin A, an inhibitor of HDAC6, enhances temozolomide induced apoptosis and reverses the malignant phenotype of glioblastoma cells, Int. J. Oncol, 54(5) (2019) 1797-1808.
  • [14] Marks D. C., Belov L., Davey M. W., Davey R. A., Kidman A. D., The MTT cell viability assay for cytotoxicity testing in multidrug-resistant human leukemic cells, Leuk. Res., 16(12) (1992) 1165-1173.
  • [15] Rizvi S., Khan S. A., Hallemeier C. L., Kelley R. K., Gores G. J., Cholangiocarcinoma-evolving concepts and therapeutic strategies, Nature Reviews Clinical Oncology, 15(2) (2018) 95-111.
  • [16] Valle J., Wasan H., Palmer D. H., Cunningham D., Anthoney A., Maraveyas A., Madhusudan S., Iveson T., Hughes S., Pereira S. P., Roughton M., Bridgewater J., ABC-02 Trial Investigators., Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer, N. Engl. J. Med., 362(14) (2010) 1273-81.
  • [17] Eberharter A., Becker P. B., Histone acetylation: A switch between repressive and permissive chromatin. Second in review on chromatin dynamics, EMBO Rep., 3(3) (2002) 224-9.
  • [18] Egger G., Liang G., Aparicio A., Jones P. A., Epigenetics in human disease and prospects for epigenetic therapy, Nature, 429(6990) (2004) 457-63.
  • [19] Cheng Y., He C., Wang M., Ma X., Mo F., Yang S., Han J., Wei X., Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials, Signal Transduct. Target. Ther., 4 (2019) 62.
  • [20] Bates S. E., Epigenetic Therapies for Cancer, N. Engl. J. Med., 383(7) (2020) 650-663.
  • [21] Dong J., Zheng N., Wang X., Tang C., Yan P., Zhou H. B., Huang J., A novel HDAC6 inhibitor exerts an anti-cancer effect by triggering cell cycle arrest and apoptosis in gastric cancer, Eur. J. Pharmacol., 828 (2018) 67-79.
  • [22] Wang G., He J., Zhao J., Yun W., Xie C., Taub J. W., Azmi A., Mohammad R. M., Dong Y., Kong W., Guo Y., Ge Y., Class I and Class II Histone Deacetylases Are Potential Therapeutic Targets for Treating Pancreatic Cancer, PLoS One, 7(12) (2012) e52095.
  • [23] Won H. R., Ryu H. W., Shin D. H., Yeon S. K., Lee D. H., Kwon S.H., A452, an HDAC6- selective inhibitor, synergistically enhances the anticancer activity of chemotherapeutic agents in colorectal cancer cells, Mol. Carcinog., 57(10) (2018) 1383- 1395.
  • [24] Su Y., Hopfinger N. R., Nguyen T. D., Pogash T. J., Santucci-Pereira J., Russo J., Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors, J. Exp. Clin. Cancer Res., 37(1) (2018) 314.
  • [25] Li Y., Shin D., Kwon S. H., Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes, FEBS Journal, 280(3) (2013) 775-93.
  • [26] Woan K. V., Lienlaf M., Perez-Villaroel P., Lee C., Cheng F., Knox T., Woods D. M., Barrios K., Powers J., Sahakian E., Wang H. W., Canales J., Marante D., Smalley K. S. M., Bergman J., Seto E., Kozikowski A., Pinilla-Ibarz J., Sarnaik A., Celis E., Weber J., Sotomayor E. M., Villagra A., Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation, Mol. Oncol., 9(7) (2015) 1447–1457.
Cumhuriyet Science Journal-Cover
  • ISSN: 2587-2680
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 2002
  • Yayıncı: SİVAS CUMHURİYET ÜNİVERSİTESİ > FEN FAKÜLTESİ