GFI‑1 overexpression promotes cell proliferation and apoptosis resistance in mycosis fungoides by repressing Bax and P21

Gu,Xiaoguang; Wang,Yimeng; Zhang,Chunlei; Liu,Yongsheng

doi:10.3892/ol.2021.12782

GFI‑1 overexpression promotes cell proliferation and apoptosis resistance in mycosis fungoides by repressing Bax and P21

Authors:
- Xiaoguang Gu
- Yimeng Wang
- Chunlei Zhang
- Yongsheng Liu
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Affiliations: Department of Dermatology and Venerology, Aviation General Hospital, Beijing 100012, P.R. China, Department of Dermatology and Venerology, Peking University Third Hospital, Beijing 100191, P.R. China
Published online on: May 11, 2021 https://doi.org/10.3892/ol.2021.12782
Article Number: 521
Copyright: © Gu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mycosis fungoides (MF) is the most common type of cutaneous T‑cell lymphoma. The majority of patients with advanced stage MF are resistant to conventional chemotherapy and thus have a poor prognosis. The transcriptional repressor growth factor independence‑1 (GFI‑1) serves an important role in the development of T‑cells. The results of the present study demonstrated that the expression of GFI‑1 at different clinical stages of MF was significantly higher compared with benign inflammatory dermatoses, and there was a significant association with disease progression. Gene knockdown of GFI‑1 results in the inhibition of Hut‑78 cell proliferation and clone formation in vitro, cell cycle arrest and spontaneous apoptosis, upregulation of cell cycle‑related P21, as well as the apoptosis‑related proteins Bax and Caspase‑3, and downregulation of CDK2. Using luciferase assays, and mutational analysis, it was demonstrated that GFI‑1 directly regulated the transcription of P21. The results of the present study highlighted a potential molecular therapeutic approach for the treatment of advanced MF.

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1	Wilcox RA: Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 91:151–165. 2016. View Article : Google Scholar : PubMed/NCBI
2	Goyal A, O'Leary D, Goyal K, Rubin N, Bohjanen K, Hordinsky M, Chen ST, Pongas G, Duncan LM and Lazaryan A: Increased risk of second primary hematologic and solid malignancies in patients with mycosis fungoides: A surveillance, epidemiology, and end results analysis. J Am Acad Dermatol. 83:404–411. 2020. View Article : Google Scholar : PubMed/NCBI
3	Zhang Y, Wang Y, Yu R, Huang Y, Su M, Xiao C, Martinka M, Dutz JP, Zhang X, Zheng Z and Zhou Y: Molecular markers of early-stage mycosis fungoides. J Invest Dermatol. 132:1698–1706. 2012. View Article : Google Scholar : PubMed/NCBI
4	Lansigan F, Choi J and Foss FM: Cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 22979–996. (x)2008. View Article : Google Scholar : PubMed/NCBI
5	Prince HM, Whittaker S and Hoppe RT: How I treat mycosis fungoides and Sezary syndrome. Blood. 114:4337–4353. 2009. View Article : Google Scholar : PubMed/NCBI
6	Zhang C, Richon V, Ni X, Talpur R and Duvic M: Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: Relevance to mechanism of therapeutic action. J Invest Dermatol. 125:1045–1052. 2005. View Article : Google Scholar : PubMed/NCBI
7	Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, Ralfkiaer E, Chimenti S, Diaz-Perez JL, Duncan LM, et al: WHO-EORTC classification for cutaneous lymphomas. Blood. 105:3768–3785. 2005. View Article : Google Scholar : PubMed/NCBI
8	Hock H, Hamblen MJ, Rooke HM, Traver D, Bronson RT, Cameron S and Orkin SH: Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity. 18:109–120. 2003. View Article : Google Scholar : PubMed/NCBI
9	Yucel R, Karsunky H, Klein-Hitpass L and Moroy T: The transcriptional repressor Gfi1 affects development of early, uncommitted c-Kit+ T cell progenitors and CD4/CD8 lineage decision in the thymus. J Exp Med. 197:831–844. 2003. View Article : Google Scholar : PubMed/NCBI
10	van der Meer LT, Jansen JH and van der Reijden BA: Gfi1 and Gfi1b: Key regulators of hematopoiesis. Leukemia. 24:1834–1843. 2010. View Article : Google Scholar : PubMed/NCBI
11	Zhu J, Jankovic D, Grinberg A, Guo L and Paul WE: Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion. Proc Natl Acad Sci USA. 103:18214–18219. 2006. View Article : Google Scholar : PubMed/NCBI
12	Rodel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsässer HP and Möröy T: The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3. EMBO J. 19:5845–5855. 2000. View Article : Google Scholar : PubMed/NCBI
13	Kazanjian A, Gross EA and Grimes HL: The growth factor independence-1 transcription factor: New functions and new insights. Crit Rev Oncol Hematol. 59:85–97. 2006. View Article : Google Scholar : PubMed/NCBI
14	Zhou LL, Zhao Y, Ringrose A, DeGeer D, Kennah E, Lin AE, Sheng G, Li XJ, Turhan A and Jiang X: AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. J Exp Med. 205:2657–2671. 2008. View Article : Google Scholar : PubMed/NCBI
15	Wang Y, Su M, Zhou LL, Tu P, Zhang X, Jiang X and Zhou Y: Deficiency of SATB1 expression in Sezary cells causes apoptosis resistance by regulating FasL/CD95L transcription. Blood. 117:3826–3835. 2011. View Article : Google Scholar : PubMed/NCBI
16	Su MW, Dorocicz I, Dragowska WH, Ho V, Li G, Voss N, Gascoyne R and Zhou Y: Aberrant expression of T-plastin in Sezary cells. Cancer Res. 63:7122–7127. 2003.PubMed/NCBI
17	Gu X, Wang Y, Zhang G, Li W and Tu P: Aberrant expression of BCL11B in mycosis fungoides and its potential role in interferon-induced apoptosis. J Dermatol. 40:596–605. 2013. View Article : Google Scholar : PubMed/NCBI
18	Campbell JJ, Clark RA, Watanabe R and Kupper TS: Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: A biologic rationale for their distinct clinical behaviors. Blood. 116:767–771. 2010. View Article : Google Scholar : PubMed/NCBI
19	van Doorn R, van Kester MS, Dijkman R, Vermeer MH, Mulder AA, Szuhai K, Knijnenburg J, Boer JM, Willemze R and Tensen CP: Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome. Blood. 113:127–136. 2009. View Article : Google Scholar : PubMed/NCBI
20	Hwang ST, Janik JE, Jaffe ES and Wilson WH: Mycosis fungoides and Sezary syndrome. Lancet. 371:945–957. 2008. View Article : Google Scholar : PubMed/NCBI
21	Dummer R, Asagoe K, Cozzio A, Burg G, Doebbeling U, Golling P, Fujii K and Urosevic M: Recent advances in cutaneous lymphomas. J Dermatol Sci. 48:157–167. 2007. View Article : Google Scholar : PubMed/NCBI
22	Wang Y, Gu X, Li W, Zhang Q and Zhang C: PAK1 overexpression promotes cell proliferation in cutaneous T cell lymphoma via suppression of PUMA and p21. J Dermatol Sci. 90:60–67. 2018. View Article : Google Scholar : PubMed/NCBI
23	Huang Y, Litvinov IV, Wang Y, Su MW, Tu P, Jiang X, Kupper TS, Dutz JP, Sasseville D and Zhou Y: Thymocyte selection-associated high mobility group box gene (TOX) is aberrantly over-expressed in mycosis fungoides and correlates with poor prognosis. Oncotarget. 5:4418–4425. 2014. View Article : Google Scholar : PubMed/NCBI
24	Ringrose A, Zhou Y, Pang E, Zhou L, Lin AE, Sheng G, Li XJ, Weng A, Su MW, Pittelkow MR and Jiang X: Evidence for an oncogenic role of AHI-1 in Sezary syndrome, a leukemic variant of human cutaneous T-cell lymphomas. Leukemia. 20:1593–1601. 2006. View Article : Google Scholar : PubMed/NCBI
25	Fu W, Yi S, Qiu L, Sun J, Tu P and Wang Y: BCL11B-Mediated epigenetic repression is a crucial target for histone deacetylase inhibitors in cutaneous T-Cell lymphoma. J Invest Dermatol. 137:1523–1532. 2017. View Article : Google Scholar : PubMed/NCBI
26	Frei GM, Kremer M, Hanschmann KM, Krause S, Albeck M, Sredni B and Schnierle BS: Antitumour effects in mycosis fungoides of the immunomodulatory, tellurium-based compound, AS101. Br J Dermatol. 158:578–586. 2008. View Article : Google Scholar : PubMed/NCBI
27	Grimes HL, Chan TO, Zweidler-McKay PA, Tong B and Tsichlis PN: The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal. Mol Cell Biol. 16:6263–6272. 1996. View Article : Google Scholar : PubMed/NCBI
28	Duan Z, Zarebski A, Montoya-Durango D, Grimes HL and Horwitz M: Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1. Mol Cell Biol. 25:10338–10351. 2005. View Article : Google Scholar : PubMed/NCBI
29	Mandal M, Bandyopadhyay D, Goepfert TM and Kumar R: Interferon-induces expression of cyclin-dependent kinase-inhibitors p21WAF1 and p27Kip1 that prevent activation of cyclin-dependent kinase by CDK-activating kinase (CAK). Oncogene. 16:217–225. 1998. View Article : Google Scholar : PubMed/NCBI
30	Abbas T, Jha S, Sherman NE and Dutta A: Autocatalytic phosphorylation of CDK2 at the activating Thr160. Cell Cycle. 6:843–852. 2007. View Article : Google Scholar : PubMed/NCBI
31	Martin-Caballero J, Flores JM, Garcia-Palencia P and Serrano M: Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. Cancer Res. 61:6234–6238. 2001.PubMed/NCBI
32	Shiohara M, el-Deiry WS, Wada M, Nakamaki T, Takeuchi S, Yang R, Chen DL, Vogelstein B and Koeffler HP: Absence of WAF1 mutations in a variety of human malignancies. Blood. 84:3781–3784. 1994. View Article : Google Scholar : PubMed/NCBI
33	Grimes HL, Gilks CB, Chan TO, Porter S and Tsichlis PN: The Gfi-1 protooncoprotein represses Bax expression and inhibits T-cell death. Proc Natl Acad Sci USA. 93:14569–14573. 1996. View Article : Google Scholar : PubMed/NCBI