Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

Zhang,Hongwei; Chi,Fenqing; Qin,Keru; Mu,Xiuli; Wang,Lieyang; Yang,Bin; Wang,Yanli; Bai,Min; Li,Zhenhua; Su,Liping; Yu,Baofeng

doi:10.3892/mmr.2021.11947

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

Authors:
- Hongwei Zhang
- Fenqing Chi
- Keru Qin
- Xiuli Mu
- Lieyang Wang
- Bin Yang
- Yanli Wang
- Min Bai
- Zhenhua Li
- Liping Su
- Baofeng Yu
View Affiliations

Affiliations: Department of Hematology, Cancer Hospital of Shanxi Province, Taiyuan, Shanxi 030013, P.R. China, Department of Biochemistry and Molecular Biology, Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
Published online on: February 26, 2021 https://doi.org/10.3892/mmr.2021.11947
Article Number: 308
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Diffuse large B‑cell lymphoma (DLBCL) is a highly heterogeneous malignant tumor type, and epigenetic modifications such as acetylation or deacetylation serve vital roles in its development. Chidamide, a novel histone deacetylase inhibitor, exerts an anticancer effect against various types of cancer. The present study aimed to evaluate the cellular effect of chidamide on a number of DLBCL cell lines and to investigate its underlying mechanism. The results demonstrated that chidamide induced the death of these cells in a concentration‑(0‑30 µmol/l) and time‑dependent (24‑72 h) manner, as determined using the Cell Counting Kit‑8 cell viability assay. Moreover, chidamide promoted cellular apoptosis, which was identified via flow cytometry and western blot analysis, with an increase in cleaved caspase‑3 expression and a decrease in Bcl‑2 expression. Chidamide treatment also decreased the expression level of STAT3 and its phosphorylation, which was accompanied by the downregulation of a class‑I histone deacetylase (HDAC) inhibitor, chidamide. Collectively, these data suggested that chidamide can be a potent therapeutic agent to treat DLBCL by inducing the apoptotic death of DLBCL cells by inhibiting the HDACs/STAT3/Bcl‑2 pathway.

View Figures

View References

1	Kubuschok B, Held G and Pfreundschuh M: Management of diffuse large B-cell lymphoma (DLBCL). Cancer Treat Res. 165:271–288. 2015. View Article : Google Scholar : PubMed/NCBI
2	Li S, Young KH and Medeiros LJ: Diffuse large B-cell lymphoma. Pathology. 50:74–87. 2018. View Article : Google Scholar : PubMed/NCBI
3	Kong Y, Chen G, Xu Z, Yang G, Li B, Wu X, Xiao W, Xie B, Hu L, Sun X, et al: Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells. Sci Rep. 6:374172016. View Article : Google Scholar : PubMed/NCBI
4	Hunt KE and Reichard KK: Diffuse large B-cell lymphoma. Arch Pathol Lab Med. 132:118–124. 2008. View Article : Google Scholar : PubMed/NCBI
5	Sehn LH and Gascoyne RD: Diffuse large B-cell lymphoma: Optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 125:22–32. 2015. View Article : Google Scholar : PubMed/NCBI
6	Mondello P and Mian M: Frontline treatment of diffuse large B-cell lymphoma: Beyond R-CHOP. Hematol Oncol. 37:333–344. 2019. View Article : Google Scholar : PubMed/NCBI
7	Pan YR, Chen CC, Chan YT, Wang HJ, Chien FT, Chen YL, Liu JL and Yang MH: STAT3-coordinated migration facilitates the dissemination of diffuse large B-cell lymphomas. Nat Commun. 9:36962018. View Article : Google Scholar : PubMed/NCBI
8	Tamma R, Ingravallo G, Albano F, Gaudio F, Annese T, Ruggieri S, Lorusso L, Errede M, Maiorano E, Specchia G and Ribatti D: STAT-3 RNA scope determination in human diffuse large B-cell lymphoma. Transl Oncol. 12:545–549. 2019. View Article : Google Scholar : PubMed/NCBI
9	Lu K, Li B, Zhang H, Xu Z, Song D, Gao L, Sun H, Li L, Wang Y, Feng Q, et al: A novel silicone derivative of natural osalmid (DCZ0858) induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway. Signal Transduct Target Ther. 5:312020. View Article : Google Scholar : PubMed/NCBI
10	Ding BB, Yu JJ, Yu RY, Mendez LM, Shaknovich R, Zhang Y, Cattoretti G and Ye BH: Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood. 111:1515–1523. 2008. View Article : Google Scholar : PubMed/NCBI
11	Moskowitz AJ and Horwitz SM: Targeting histone deacetylases in T-cell lymphoma. Leuk Lymphoma. 58:1306–1319. 2017. View Article : Google Scholar : PubMed/NCBI
12	Bai X, Jiang H, Han G and He Q: Chidamide suppresses the glycolysis of triple negative breast cancer cells partially by targeting the miR33a5pLDHA axis. Mol Med Rep. 20:1857–1865. 2019.PubMed/NCBI
13	Sun Y, Li J, Xu Z, Xu J, Shi M and Liu P: Chidamide, a novel histone deacetylase inhibitor, inhibits multiple myeloma cells proliferation through succinate dehydrogenase subunit A. Am J Cancer Res. 9:574–584. 2019.PubMed/NCBI
14	Wu YF, Ou CC, Chien PJ, Chang HY, Ko JL and Wang BY: Chidamide-induced ROS accumulation and miR-129-3p-dependent cell cycle arrest in non-small lung cancer cells. Phytomedicine. 56:94–102. 2019. View Article : Google Scholar : PubMed/NCBI
15	Ubink I, Bolhaqueiro ACF, Elias SG, Raats DAE, Constantinides A, Peters NA, Wassenaar ECE, de Hingh IHJT, Rovers KP, van Grevenstein WMU, et al: Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy. Br J Surg. 106:1404–1414. 2019. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
17	Best S, Hashiguchi T, Kittai A, Bruss N, Paiva C, Okada C, Liu T, Berger A and Danilov AV: Targeting ubiquitin-activating enzyme induces ER stress-mediated apoptosis in B-cell lymphoma cells. Blood Adv. 3:51–62. 2019. View Article : Google Scholar : PubMed/NCBI
18	Jin CY, Moon DO, Choi YH, Lee JD and Kim GY: Bcl-2 and caspase-3 are major regulators in Agaricus blazei-induced human leukemic U937 cell apoptosis through dephoshorylation of Akt. Biol Pharm Bull. 30:1432–1437. 2007. View Article : Google Scholar : PubMed/NCBI
19	Ning ZQ, Li ZB, Newman MJ, Shan S, Wang XH, Pan DS, Zhang J, Dong M, Du X and Lu XP: Chidamide (CS055/HBI-8000): A new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol. 69:901–909. 2012. View Article : Google Scholar : PubMed/NCBI
20	Li Y and Seto E: HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med. 6:a0268312016. View Article : Google Scholar : PubMed/NCBI
21	Williams SA, Chen LF, Kwon H, Ruiz-Jarabo CM, Verdin E and Greene WC: NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25:139–149. 2006. View Article : Google Scholar : PubMed/NCBI
22	Lee SH, Yoo C, Im S, Jung JH, Choi HJ and Yoo J: Expression of histone deacetylases in diffuse large B-cell lymphoma and its clinical significance. Int J Med Sci. 11:994–1000. 2014. View Article : Google Scholar : PubMed/NCBI
23	Gloghini A, Buglio D, Khaskhely NM, Georgakis G, Orlowski RZ, Neelapu SS, Carbone A and Younes A: Expression of histone deacetylases in lymphoma: Implication for the development of selective inhibitors. Br J Haematol. 147:515–525. 2009. View Article : Google Scholar : PubMed/NCBI
24	Wang M, Fang X and Wang X: Emerging role of histone deacetylase inhibitors in the treatment of diffuse large B-cell lymphoma. Leuk Lymphoma. 61:763–775. 2020. View Article : Google Scholar : PubMed/NCBI
25	Gao S, Li X, Zang J, Xu W and Zhang Y: Preclinical and clinical studies of chidamide (CS055/HBI-8000), an orally available subtype-selective HDAC inhibitor for cancer therapy. Anticancer Agents Med Chem. 17:802–812. 2017. View Article : Google Scholar : PubMed/NCBI
26	Chan TS, Tse E and Kwong YL: Chidamide in the treatment of peripheral T-cell lymphoma. Onco Targets Therapy. 10:347–352. 2017. View Article : Google Scholar
27	Li Q, Huang J, Ou Y, Li Y and Wu Y: Progressive diffuse large B-cell lymphoma with TP53 gene mutation treated with chidamide-based chemotherapy. Immunotherapy. 11:265–272. 2019. View Article : Google Scholar : PubMed/NCBI
28	Miao Y, Medeiros LJ, Li Y, Li J and Young KH: Genetic alterations and their clinical implications in DLBCL. Nat Rev Clin Oncol. 16:634–652. 2019. View Article : Google Scholar : PubMed/NCBI
29	Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, et al: Oncogenically active MYD88 mutations in human lymphoma. Nature. 470:115–119. 2011. View Article : Google Scholar : PubMed/NCBI
30	Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, Bertoni F, Ponzoni M, Scandurra M, Califano A, et al: Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature. 459:717–721. 2009. View Article : Google Scholar : PubMed/NCBI
31	Guan XW, Wang HQ, Ban WW, Chang Z, Chen HZ, Jia L and Liu FT: Novel HDAC inhibitor Chidamide synergizes with Rituximab to inhibit diffuse large B-cell lymphoma tumour growth by upregulating CD20. Cell Death Dis. 11:202020. View Article : Google Scholar : PubMed/NCBI
32	Teng Y, Ross JL and Cowell JK: The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT. 3:e280862014.PubMed/NCBI
33	Sgrignani J, Garofalo M, Matkovic M, Merulla J, Catapano CV and Cavalli A: Structural biology of STAT3 and its implications for anticancer therapies development. Int J Mol Sci. 19:15912018. View Article : Google Scholar
34	Gharibi T, Babaloo Z, Hosseini A, Abdollahpour-Alitappeh M, Hashemi V, Marofi F, Nejati K and Baradaran B: Targeting STAT3 in cancer and autoimmune diseases. Eur J Pharmacol. 878:1731072020. View Article : Google Scholar : PubMed/NCBI
35	Mohassab AM, Hassan HA, Abdelhamid D and Abdel-Aziz M: STAT3 transcription factor as target for anti-cancer therapy. Pharmacol Rep. 72:1101–1124. 2020. View Article : Google Scholar : PubMed/NCBI
36	Ni L, Wang L, Yao C, Ni Z, Liu F, Gong C, Zhu X, Yan X, Watowich SS, Lee DA and Zhu S: The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3. Sci Rep. 7:452662017. View Article : Google Scholar : PubMed/NCBI
37	Hoesel B and Schmid JA: The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 12:862013. View Article : Google Scholar : PubMed/NCBI
38	Lu L, Zhu F, Li Y, Kimpara S, Hoang NM, Pourdashti S and Rui L: Inhibition of the STAT3 target SGK1 sensitizes diffuse large B cell lymphoma cells to AKT inhibitors. Blood Cancer J. 9:432019. View Article : Google Scholar : PubMed/NCBI
39	Belo Y, Mielko Z, Nudelman H, Afek A, Ben-David O, Shahar A, Zarivach R, Gordan R and Arbely E: Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine. Biochim Biophys Acta Gen Subj. 1863:1343–1350. 2019. View Article : Google Scholar : PubMed/NCBI
40	Zhang R, Lyu C, Lu W, Pu Y, Jiang Y and Deng Q: Synergistic effect of programmed death-1 inhibitor and programmed death-1 ligand-1 inhibitor combined with chemotherapeutic drugs on DLBCL cell lines in vitro and in vivo. Am J Cancer Res. 10:2800–2812. 2020.PubMed/NCBI