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Current Medicinal Chemistry

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ISSN (Online): 1875-533X

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Research Article

YF343, A Novel Histone Deacetylase Inhibitor, Combined with CQ to Inhibit- Autophagy, Contributes to Increased Apoptosis in Triple- Negative Breast Cancer

Author(s): Na Liu, Tingting Luo, Jing Zhang, Li-na Han, Wen-qi Duan, Wen-xia Lu, Huiran Qiu, Yan Lin, Yong-mei Wu, Hua Zhang, Fei-fei Yang* and Di Ge*

Volume 30, Issue 40, 2023

Published on: 08 March, 2023

Page: [4605 - 4621] Pages: 17

DOI: 10.2174/0929867330666230120152815

Price: $65

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Abstract

Background: Compounds that target tumor epigenetic events are likely to constitute a prominent strategy for anticancer treatment. Histone deacetylase inhibitors (HDACis) have been developed as prospective candidates in anticancer drug development, and currently, many of them are under clinical investigation. We assessed the anticancer efficacy of a now hydroxamate-based HDACi, YF-343, in triple-negative breast cancer development and studied its potential mechanisms.

Methods: YF-343 was estimated as a novel HDACi by the HDACi drug screening kit. The biological effects of YF-343 in a panel of breast cancer cell lines were analyzed by Western blot and flow cytometry. YF-343 exhibited notable cytotoxicity, promoted apoptosis, and induced cell cycle arrest. Furthermore, it also induced autophagy, which plays a pro-survival role in breast cancer cells.

Results: The combination of YF-343 with an autophagy inhibitor chloroquine (CQ) significantly suppressed breast tumor progression as compared to the YF-343 treatment alone both in vitro and in vivo. Mechanistically, the molecular mechanism of YF-343 on autophagy was elucidated by gene chip expression profiles, qPCR analysis, luciferase reporter gene assay, chromatin immunoprecipitation assays, immunohistochemical analysis, and other methods. E2F7, a transcription factor, promoted the expression of ATG2A via binding to the ATG2A promoter region and then induced autophagy in triple-negative breast cancer cells treated with YF-343.

Conclusion: Our studies have illustrated the mechanisms for potential action of YF-343 on tumor growth in breast cancer models with pro-survival autophagy. The combination therapy of YF-343 and CQ maybe a promising strategy for breast cancer therapy.

Keywords: HDACi, triple-negative breast cancer, apoptosis, autophagy, chloroquine, E2F7.

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[1]
Podo, F.; Buydens, L.M.C.; Degani, H.; Hilhorst, R.; Klipp, E.; Gribbestad, I.S.; Van Huffel, S.; van Laarhoven, H.W.; Luts, J.; Monleon, D.; Postma, G.J.; Schneiderhan-Marra, N.; Santoro, F.; Wouters, H.; Russnes, H.G.; Sørlie, T.; Tagliabue, E.; Børresen-Dale, A.L. Triple-negative breast cancer: present challenges and new perspectives. Mol. Oncol., 2010, 4(3), 209-229.
[http://dx.doi.org/10.1016/j.molonc.2010.04.006] [PMID: 20537966]
[2]
Li, H.; Chen, Y.; Wang, X.; Tang, L.; Guan, X. T1-2N0M0 triple-negative breast cancer treated with breast-conserving therapy has better survival compared to mastectomy: A SEER population-based retrospective analysis. Clin. Breast Cancer, 2019, 19(6), e669-e682.
[http://dx.doi.org/10.1016/j.clbc.2019.05.011] [PMID: 31375327]
[3]
King, T.A.; Li, W.; Brogi, E.; Yee, C.J.; Gemignani, M.L.; Olvera, N.; Levine, D.A.; Norton, L.; Robson, M.E.; Offit, K.; Borgen, P.I.; Boyd, J. Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. Ann. Surg. Oncol., 2007, 14(9), 2510-2518.
[http://dx.doi.org/10.1245/s10434-007-9372-1] [PMID: 17597348]
[4]
Huang, Y.; Nayak, S.; Jankowitz, R.; Davidson, N.E.; Oesterreich, S. Epigenetics in breast cancer: what’s new? Breast Cancer Res., 2011, 13(6), 225.
[http://dx.doi.org/10.1186/bcr2925] [PMID: 22078060]
[5]
Feinberg, A.P.; Koldobskiy, M.A.; Göndör, A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet., 2016, 17(5), 284-299.
[http://dx.doi.org/10.1038/nrg.2016.13] [PMID: 26972587]
[6]
Tessarz, P.; Kouzarides, T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol., 2014, 15(11), 703-708.
[http://dx.doi.org/10.1038/nrm3890] [PMID: 25315270]
[7]
Li, Y.; Seto, E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med., 2016, 6(10), a026831.
[http://dx.doi.org/10.1101/cshperspect.a026831] [PMID: 27599530]
[8]
Clements, M.E.; Holtslander, L.; Edwards, C.; Todd, V.; Dooyema, S.D.R.; Bullock, K.; Bergdorf, K.; Zahnow, C.A.; Connolly, R.M.; Johnson, R.W. HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. Oncogene, 2021, 40(34), 5314-5326.
[http://dx.doi.org/10.1038/s41388-021-01931-1] [PMID: 34247191]
[9]
Hou, F.; Li, D.; Yu, H.; Kong, Q. The mechanism and potential targets of class II HDACs in angiogenesis. J. Cell. Biochem., 2018, 119(4), 2999-3006.
[http://dx.doi.org/10.1002/jcb.26476] [PMID: 29091298]
[10]
Khan, O.; La Thangue, N.B. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol. Cell Biol., 2012, 90(1), 85-94.
[http://dx.doi.org/10.1038/icb.2011.100] [PMID: 22124371]
[11]
Gatla, H.R.; Zou, Y.; Uddin, M.M.; Singha, B.; Bu, P.; Vancura, A.; Vancurova, I. Histone deacetylase (HDAC) inhibition induces IκB kinase (IKK)-dependent interleukin-8/CXCL8 expression in dvarian cancer cells. J. Biol. Chem., 2017, 292(12), 5043-5054.
[http://dx.doi.org/10.1074/jbc.M116.771014] [PMID: 28167529]
[12]
Shan, P.; Yang, F.; Qi, H.; Hu, Y.; Zhu, S.; Sun, Z.; Zhang, Z.; Wang, C.; Hou, C.; Yu, J.; Wang, L.; Zhou, Z.; Li, P.; Zhang, H.; Wang, K. Alteration of MDM2 by the small molecule YF438 exerts antitumor effects in triple-negative breast cancer. Cancer Res., 2021, 81(15), 4027-4040.
[http://dx.doi.org/10.1158/0008-5472.CAN-20-0922] [PMID: 33985974]
[13]
Carew, J.S.; Giles, F.J.; Nawrocki, S.T. Histone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapy. Cancer Lett., 2008, 269(1), 7-17.
[http://dx.doi.org/10.1016/j.canlet.2008.03.037] [PMID: 18462867]
[14]
Wagner, J.M.; Hackanson, B.; Lübbert, M.; Jung, M. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin. Epigenetics, 2010, 1(3-4), 117-136.
[http://dx.doi.org/10.1007/s13148-010-0012-4] [PMID: 21258646]
[15]
Eskelinen, E.L. The dual role of autophagy in cancer. Curr. Opin. Pharmacol., 2011, 11(4), 294-300.
[http://dx.doi.org/10.1016/j.coph.2011.03.009] [PMID: 21498118]
[16]
Yang, Z.J.; Chee, C.E.; Huang, S.; Sinicrope, F. Autophagy modulation for cancer therapy. Cancer Biol. Ther., 2011, 11(2), 169-176.
[http://dx.doi.org/10.4161/cbt.11.2.14663] [PMID: 21263212]
[17]
Roberts, J.L.; Poklepovic, A.; Booth, L.; Dent, P. The multi-kinase inhibitor lenvatinib interacts with the HDAC inhibitor entinostat to kill liver cancer cells. Cell. Signal., 2020, 70, 109573.
[http://dx.doi.org/10.1016/j.cellsig.2020.109573] [PMID: 32087304]
[18]
Mrakovcic, M.; Kleinheinz, J.; Fröhlich, L. Histone deacetylase inhibitor-induced autophagy in tumor cells: Implications for p53. Int. J. Mol. Sci., 2017, 18(9), 1883.
[http://dx.doi.org/10.3390/ijms18091883] [PMID: 30563957]
[19]
Sun, A.; Bagella, L.; Tutton, S.; Romano, G.; Giordano, A. From G0 to S phase: A view of the roles played by the retinoblastoma (Rb) family members in the Rb-E2F pathway. J. Cell. Biochem., 2007, 102(6), 1400-1404.
[http://dx.doi.org/10.1002/jcb.21609] [PMID: 17979151]
[20]
Polager, S.; Ginsberg, D. E2F – at the crossroads of life and death. Trends Cell Biol., 2008, 18(11), 528-535.
[http://dx.doi.org/10.1016/j.tcb.2008.08.003] [PMID: 18805009]
[21]
Gediya, L.K.; Chopra, P.; Purushottamachar, P.; Maheshwari, N.; Njar, V.C.O. A new simple and high-yield synthesis of suberoylanilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells. J. Med. Chem., 2005, 48(15), 5047-5051.
[http://dx.doi.org/10.1021/jm058214k] [PMID: 16033284]
[22]
Li, J.J.; Zhang, T.; Yang, F.F.; He, Y.; Dai, F.J.; Gao, D.; Chen, Y.; Liu, M.; Yi, Z. Inhibition of breast cancerprogression by a novelhistone deacetylaseinhibitor, LW479, bydown-regulatingEGFR expression. Br. J. Pharmacol., 2015, 15, 3817-3810.
[http://dx.doi.org/10.1111/bph.13165] [PMID: 25884486]
[23]
Australian Bureau of Statistics. The website Australian National Statistical Service Sample Calculator. 2018. Available from: http://www.abs.gov.au/websitedbs/ D3310114. nsf/Home/2016%20TableBuilder/
[24]
Minucci, S.; Pelicci, P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer, 2006, 6(1), 38-51.
[http://dx.doi.org/10.1038/nrc1779] [PMID: 16397526]
[25]
Mrakovcic, M.; Fröhlich, L.F. Molecular determinants of cancer therapy resistance to HDAC inhibitor-induced autophagy. Cancers (Basel), 2019, 12(1), 109.
[http://dx.doi.org/10.3390/cancers12010109] [PMID: 31906235]
[26]
Wu, N.; Li, J.; Luo, H.; Wang, D.; Bai, X. Hydroxysafflor yellow A promotes apoptosis via blocking autophagic flux in liver cancer. Biomed. Pharmacother., 2021, 136, 111227.
[http://dx.doi.org/10.1016/j.biopha.2021.111227] [PMID: 33485070]
[27]
de Bruin, A.; A Cornelissen, P.W.; Kirchmaier, B.C.; Mokry, M.; Iich, E.; Nirmala, E.; Liang, K.H.; D Végh, A.M.; Scholman, K.T.; Groot Koerkamp, M.J.; Holstege, F.C.; Cuppen, E.; Schulte-Merker, S.; Bakker, W.J. Genome-wide analysis reveals NRP1 as a direct HIF1α-E2F7 target in the regulation of motorneuron guidance in vivo. Nucleic Acids Res., 2016, 44(8), 3549-3566.
[http://dx.doi.org/10.1093/nar/gkv1471] [PMID: 26681691]
[28]
Wong, K.K. DNMT1: A key drug target in triple-negative breast cancer. Semin. Cancer Biol., 2021, 72, 198-213.
[http://dx.doi.org/10.1016/j.semcancer.2020.05.010] [PMID: 32461152]
[29]
Yin, L.; Duan, J.J.; Bian, X.W.; Yu, S. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res., 2020, 22(1), 61.
[http://dx.doi.org/10.1186/s13058-020-01296-5] [PMID: 32517735]
[30]
Gupta, G.K.; Collier, A.L.; Lee, D.; Hoefer, R.A.; Zheleva, V.; Siewertsz van Reesema, L.L.; Tang-Tan, A.M.; Guye, M.L.; Chang, D.Z.; Winston, J.S.; Samli, B.; Jansen, R.J.; Petricoin, E.F.; Goetz, M.P.; Bear, H.D.; Tang, A.H. Perspectives on triple-negative breast cancer: current treatment strategies, unmet needs, and potential targets for future therapies. Cancers (Basel), 2020, 12(9), 2392.
[http://dx.doi.org/10.3390/cancers12092392] [PMID: 32846967]
[31]
Li, Y.; Wang, S.; Wei, X.; Zhang, S.; Song, Z.; Chen, X.; Zhang, J. Role of inhibitor of yes-associated protein 1 in triple-negative breast cancer with taxol-based chemoresistance. Cancer Sci., 2019, 110(2), 561-567.
[http://dx.doi.org/10.1111/cas.13888] [PMID: 30467925]
[32]
Shao, Y.; Gao, Z.; Marks, P.A.; Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl. Acad. Sci. USA, 2004, 101(52), 18030-18035.
[http://dx.doi.org/10.1073/pnas.0408345102] [PMID: 15596714]
[33]
Watanabe, M.; Adachi, S.; Matsubara, H.; Imai, T.; Yui, Y.; Mizushima, Y.; Hiraumi, Y.; Watanabe, K.; Kamitsuji, Y.; Toyokuni, S.; Hosoi, H.; Sugimoto, T.; Toguchida, J.; Nakahata, T. Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation. Int. J. Cancer, 2009, 124(1), 55-67.
[http://dx.doi.org/10.1002/ijc.23897] [PMID: 18821579]
[34]
Taylor, M.A.; Das, B.C.; Ray, S.K. Targeting autophagy for combating chemoresistance and radioresistance in glioblastoma. Apoptosis, 2018, 23(11-12), 563-575.
[http://dx.doi.org/10.1007/s10495-018-1480-9] [PMID: 30171377]
[35]
Mrakovcic, M.; Kleinheinz, J.; Fröhlich, L.F. p53 at the crossroads between different types of HDAC inhibitor-mediated cancer cell death. Int. J. Mol. Sci., 2019, 20(10), 2415.
[http://dx.doi.org/10.3390/ijms20102415] [PMID: 31096697]
[36]
Hamed, H.A.; Das, S.K.; Sokhi, U.K.; Park, M.A.; Cruickshanks, N.; Archer, K.; Ogretmen, B.; Grant, S.; Sarkar, D.; Fisher, P.B.; Dent, P. Combining histone deacetylase inhibitors with MDA-7/IL-24 enhances killing of renal carcinoma cells. Cancer Biol. Ther., 2013, 14(11), 1039-1049.
[http://dx.doi.org/10.4161/cbt.26110] [PMID: 24025359]
[37]
Yang, P.M.; Chen, C.C. Life or death? Autophagy in anticancer therapies with statins and histone deacetylase inhibitors. Autophagy, 2011, 7(1), 107-108.
[http://dx.doi.org/10.4161/auto.7.1.13988] [PMID: 21057221]
[38]
Stankov, M.V.; El Khatib, M.; Kumar Thakur, B.; Heitmann, K.; Panayotova-Dimitrova, D.; Schoening, J.; Bourquin, J.P.; Schweitzer, N.; Leverkus, M.; Welte, K.; Reinhardt, D.; Li, Z.; Orkin, S.H.; Behrens, G.M.N.; Klusmann, J.H. Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy. Leukemia, 2014, 28(3), 577-588.
[http://dx.doi.org/10.1038/leu.2013.264] [PMID: 24080946]
[39]
Lapierre, L.R.; Kumsta, C.; Sandri, M.; Ballabio, A.; Hansen, M. Transcriptional and epigenetic regulation of autophagy in aging. Autophagy, 2015, 11(6), 867-880.
[http://dx.doi.org/10.1080/15548627.2015.1034410] [PMID: 25836756]
[40]
Chen, X.; Zhang, Y.; Shi, Y.; Lian, H.; Tu, H.; Han, S.; Yin, J.; Peng, B.; Zhou, B.; He, X.; Liu, W. MiR-129 triggers autophagic flux by regulating a novel Notch-1/ E2F7/Beclin-1 axis to impair the viability of human malignant glioma cells. Oncotarget, 2016, 7(8), 9222-9235.
[http://dx.doi.org/10.18632/oncotarget.7003] [PMID: 26824182]
[41]
Sun, C.C.; Li, S.J.; Hu, W.; Zhang, J.; Zhou, Q.; Liu, C.; Li, L.L.; Song, Y.Y.; Zhang, F.; Chen, Z.L.; Li, G.; Bi, Z.Y.; Bi, Y.Y.; Gong, F.Y.; Bo, T.; Yuan, Z.P.; Hu, W.D. Comprehensive analysis of the expression and prognosis for E2Fs in human breast cancer. Mol. Ther., 2019, 27, 1153-1165.
[http://dx.doi.org/10.1016/j.ymthe.2019.03.019] [PMID: 31010740]
[42]
Lammens, T.; Li, J.; Leone, G.; De Veylder, L. Atypical E2Fs: new players in the E2F transcription factor family. Trends Cell Biol., 2009, 19(3), 111-118.
[http://dx.doi.org/10.1016/j.tcb.2009.01.002] [PMID: 19201609]
[43]
Morgunova, E.; Yin, Y.; Jolma, A.; Dave, K.; Schmierer, B.; Popov, A.; Eremina, N.; Nilsson, L.; Taipale, J. Structural insights into the DNA-binding specificity of E2F family transcription factors. Nat. Commun., 2015, 6(1), 10050.
[http://dx.doi.org/10.1038/ncomms10050] [PMID: 26632596]
[44]
Weijts, B.G.M.W.; Westendorp, B.; Hien, B.T.; Martínez-López, L.M.; Zijp, M.; Thurlings, I.; Thomas, R.E.; Schulte-Merker, S.; Bakker, W.J.; de Bruin, A. A typical E2Fs inhibit tumor angiogenesis. Oncogene, 2018, 37(2), 271-276.
[http://dx.doi.org/10.1038/onc.2017.336] [PMID: 28925392]
[45]
Moon, N.S.; Dyson, N. E2F7 and E2F8 keep the E2F family in balance. Dev. Cell, 2008, 14(1), 1-3.
[http://dx.doi.org/10.1016/j.devcel.2007.12.017] [PMID: 18194644]
[46]
Staberg, M.; Michaelsen, S.R.; Rasmussen, R.D.; Villingshøj, M.; Poulsen, H.S.; Hamerlik, P. Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine. Cell Oncol. (Dordr.), 2017, 40(1), 21-32.
[http://dx.doi.org/10.1007/s13402-016-0301-9] [PMID: 27766591]
[47]
Lopez, G.; Torres, K.; Lev, D. Autophagy blockade enhances HDAC inhibitors’ pro-apoptotic effects. Autophagy, 2011, 7(4), 440-441.
[http://dx.doi.org/10.4161/auto.7.4.14680] [PMID: 21224727]
[48]
Körholz, K.; Ridinger, J.; Krunic, D.; Najafi, S.; Gerloff, X.F.; Frese, K.; Meder, B.; Peterziel, H.; VegaRubindeCelis, S.; Witt, Ol.; Oehme, I. Broad-spectrum HDAC inhibitors promote autophagy through FOXO transcription factors in neuroblastoma. Cells, 2021, 10(5), 1001.

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