Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission

Xiao-Ling Liang; Lan Ouyang; Nan-Nan Yu; Zheng-Hua Sun; Zi-Kang Gui; Yu-Long Niu; Qing-Yu He; Jing Zhang; Yang Wang

doi:10.1016/j.jpha.2023.06.005

Volume 13 Issue 10

Oct. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(10): 1168-1182

Xiao-Ling Liang, Lan Ouyang, Nan-Nan Yu, Zheng-Hua Sun, Zi-Kang Gui, Yu-Long Niu, Qing-Yu He, Jing Zhang, Yang Wang. Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission[J]. Journal of Pharmaceutical Analysis, 2023, 13(10): 1168-1182. doi: 10.1016/j.jpha.2023.06.005

Citation:

Xiao-Ling Liang, Lan Ouyang, Nan-Nan Yu, Zheng-Hua Sun, Zi-Kang Gui, Yu-Long Niu, Qing-Yu He, Jing Zhang, Yang Wang. Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission[J]. Journal of Pharmaceutical Analysis, 2023, 13(10): 1168-1182. doi: 10.1016/j.jpha.2023.06.005

Citation:

Xiao-Ling Liang, Lan Ouyang, Nan-Nan Yu, Zheng-Hua Sun, Zi-Kang Gui, Yu-Long Niu, Qing-Yu He, Jing Zhang, Yang Wang. Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission[J]. Journal of Pharmaceutical Analysis, 2023, 13(10): 1168-1182. doi: 10.1016/j.jpha.2023.06.005

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Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission

doi: 10.1016/j.jpha.2023.06.005

a. MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China;
b. Department of Radiology, The First Affiliated Hospital of Jinan University and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant Nos.: 82103208, and 82002948), the Guangdong Basic and Applied Basic Research Foundation (Grant Nos.: 2022A1515220212, and 2023A1515030115), National Key R & D Program of China (Grant No.: 2020YFE0202200) and Jinan University National College Students' Innovation and Entrepreneurship Training Program (Program No.: 202110559085).

Received Date: Dec. 21, 2022
Accepted Date: Jun. 09, 2023
Rev Recd Date: May 28, 2023
Publish Date: Oct. 30, 2023

Abstract

Abstract

Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of excessively asymmetric mitofission-associated cell death (MFAD) by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy. By screening a series of pan-inhibitors, we identified pracinostat, a pan-histone deacetylase (HDAC) inhibitor, as a novel MFAD inducer, that exhibited a significant anticancer effect on colorectal cancer (CRC) in vivo and in vitro. Pracinostat increased the expression of cyclin-dependent kinase 5 (CDK5) and induced its acetylation at residue lysine 33, accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1 (Drp1)-mediated mitochondrial peripheral fission. CRC cells with high level of CDK5 (CDK5-high) displayed midzone mitochondrial division that was associated with oncogenic phenotype, but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells. Mechanistically, pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor (MFF) to mitochondrial fission 1 protein (FIS1). Thus, our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.
- HDAC inhibitor,
- Pracinostat,
- CDK5,
- Mitochondrial fission,
- Acetylation,
- Drp1

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References(33)

References

D.T. Sessions, D.F. Kashatus, Mitochondrial dynamics in cancer stem cells, Cell. Mol. Life Sci. 78 (2021) 3803-3816.

F. Kraus, K. Roy, T.J. Pucadyil, et al., Function and regulation of the divisome for mitochondrial fission, Nature 590 (2021) 57-66.

M. Tang, M. Yang, G. Wu, et al., Epigenetic induction of mitochondrial fission is required for maintenance of liver cancer-initiating cells, Cancer Res. 81 (2021) 3835-3848.

T. Kleele, T. Rey, J. Winter, et al., Distinct fission signatures predict mitochondrial degradation or biogenesis, Nature 593 (2021) 435-439.

Y. Sun, Y. Yang, Y. Hu, et al., Inhibition of nuclear deacetylase Sirtuin-1 induces mitochondrial acetylation and calcium overload leading to cell death, Redox Biol. 53 (2022), 102334.

L. Cappellacci, D.R. Perinelli, F. Maggi, et al., Recent progress in histone deacetylase inhibitors as anticancer agents, Curr. Med. Chem. 27 (2020) 2449-2493.

N.K. Sedky, A.A. Hamdan, S. Emad, et al., Insights into the therapeutic potential of histone deacetylase inhibitor/immunotherapy combination regimens in solid tumors, Clin. Transl. Oncol. 24 (2022) 1262-1273.

G.M. Matthews, P. Mehdipour, L.A. Cluse, et al., Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies, Blood 126 (2015) 2392-2403.

N. Garmpis, C. Damaskos, A. Garmpi, et al., Histone deacetylases and their inhibitors in colorectal cancer therapy: Current evidence and future considerations, Curr. Med. Chem. 29 (2022) 2979-2994.

S.A. Ganai, Histone deacetylase inhibitor pracinostat in doublet therapy: A unique strategy to improve therapeutic efficacy and to tackle Herculean cancer chemoresistance, Pharm. Biol. 54 (2016) 1926-1935.

H. Wang, N. Yu, D. Chen, et al., Discovery of (2E)-3-2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile, J. Med. Chem. 54 (2011) 4694-4720.

J. Chen, N. Li, B. Liu, et al., Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathways, Life Sci. 248 (2020), 117469.

G.B. Gao, Y. Sun, R. Fang, et al., Post-translational modifications of CDK5 and their biological roles in cancer, Mol. Biomed. 2 (2021), 22.

K. Zhuang, J. Zhang, M. Xiong, et al., CDK5 functions as a tumor promoter in human colorectal cancer via modulating the ERK5-AP-1 axis, Cell Death Dis. 7 (2016), e2415.

Y. Wang, J. Zhang, Y.J. Li, et al., MEST promotes lung cancer invasion and metastasis by interacting with VCP to activate NF-κB signaling, J. Exp. Clin. Cancer Res. 40 (2021), 301.

Z. Huang, S. Zhu, Z. Han, et al., Proteome-wide analysis reveals TFEB targets for establishment of a prognostic signature to predict clinical outcomes of colorectal cancer, Cancers (Basel) 15 (2023),744.

A.J. Valente, L.A. Maddalena, E.L. Robb, et al., A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture, Acta Histochem. 119 (2017) 315-326.

H. Hu, G. Gao, X. He, et al., Targeting ARF1-IQGAP1 interaction to suppress colorectal cancer metastasis and vemurafenib resistance, J. Adv. Res. (2022).

J. Zhang, Y. Zhou, N. Li, et al., Curcumol overcomes TRAIL resistance of non-small cell lung cancer by targeting NRH:Quinone oxidoreductase 2 (NQO2), Adv. Sci. 7 (2020), 2002306.

M. Adebayo, S. Singh, A.P. Singh, et al., Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis, FASEB J. 35 (2021), e21620.

R. Rong, X. Xia, H. Peng, et al., Cdk5-mediated Drp1 phosphorylation drives mitochondrial defects and neuronal apoptosis in radiation-induced optic neuropathy, Cell Death Dis. 11 (2020), 720.

V. Novotny-Diermayr, S. Hart, K.C. Goh, et al., The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML, Blood Cancer J. 2 (2012), e69.

F. Bray, J. Ferlay, I. Soerjomataram, et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA A Cancer J. Clin. 68 (2018) 394-424.

M. Arnold, M.S. Sierra, M. Laversanne, et al., Global patterns and trends in colorectal cancer incidence and mortality, Gut 66 (2017) 683-691.

Z. Li, L. Mao, B. Yu, et al., GB7 acetate, a galbulimima alkaloid from Galbulimima belgraveana, possesses anticancer effects in colorectal cancer cells, J. Pharm. Anal. 12 (2022) 339-349.

Y. Wang, Y. Chen, G. Gao, et al., Polyphyllin D "punctures" hypertrophic lysosomes to reverse drug resistance of hepatocellular carcinoma by targeting acid sphingomyelinase, Mol. Ther. (2023).

Y. Bei, N. Cheng, T. Chen, et al., CDK5 inhibition abrogates TNBC stem-cell property and enhances anti-PD-1 therapy, Adv. Sci. 7 (2020), 2001417.

W. Li, M.E. Allen, Y. Rui, et al., p39 is responsible for increasing cdk5 activity during postnatal neuron differentiation and governs neuronal network formation and epileptic responses, J. Neurosci. 36 (2016) 11283-11294.

J. Lee, Y.U. Ko, Y. Chung, et al., The acetylation of cyclin-dependent kinase 5 at lysine 33 regulates kinase activity and neurite length in hippocampal neurons, Sci. Rep. 8 (2018), 13676.

T. Guevara, M. Sancho, E. Perez-Paya, et al., Role of CDK5/cyclin complexes in ischemia-induced death and survival of renal tubular cells, Cell Cycle 13 (2014) 1617-1626.

J. Rashidian, M.W. Rousseaux, K. Venderova, et al., Essential role of cytoplasmic cdk5 and Prx2 in multiple ischemic injury models, in vivo, J. Neurosci. 29 (2009) 12497-12505.

J.S. Lee, Y.G. Yoon, S.H. Yoo, et al., Histone deacetylase inhibitors induce mitochondrial elongation, J. Cell. Physiol. 227 (2012) 2856-2869.

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