| Citation: |
CAI Qing-hua, WANG Cai-xia, CHEN Cun-te. The Effect of NPL4-Targeted Inhibitor Disulfiram on the Expression of Genes Related to the Ubiquitin-Proteasome Pathway in T-Cell Malignancies[J]. Journal of Evidence-Based Medicine, 2024, 24(2): 115-123. DOI: 10.12019/j.issn.1671-5144.202404028
|
Our previous studies have demonstrated that disulfiram (DSF) exerts antitumor effects on T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), through the ubiquitin-proteasome pathway mediated by nuclear protein localization protein 4 homolog (NPL4). This study aims to investigate the regulatory effects of disulfiram on the expression of genes related to the ubiquitin-proteasome pathway in T-cell malignancies, providing a basis for precision targeted therapy of T-cell malignancies.
Jurkat cells, a T-ALL cell line, were treated with 0.4 μM disulfiram for 48 hours. Transcriptome sequencing was performed to analyze differentially expressed genes, and real-time quantitative PCR was used to validate the relative expression levels of these genes in 10 T-cell malignancy samples (GZFPH dataset). Additionally, transcriptome sequencing data from 262 cases of T-ALL and 140 cases of TCL were downloaded from the TARGET and GSE58445 databases for survival analysis.
After treating Jurkat cells with 0.4 μM disulfiram for 48 hours, 86 genes were downregulated and 35 genes were upregulated in the ubiquitin-proteasome pathway. Among these genes, univariate Cox regression and survival curve analysis revealed that only low expression of ubiquitin-conjugating enzyme E2 J1 (UBE2J1) was associated with poor prognosis in patients with T-ALL and TCL in both the TARGET and GSE58445 datasets (P < 0.05). When incorporating UBE2J1 expression level, age, and gender into univariate and multivariate Cox regression analyses, low expression of UBE2J1 emerged as an independent prognostic factor for patients with T-ALL and TCL (P < 0.05).
Disulfiram can regulate the expression of the UBE2J1 gene, and its low expression is associated with poor prognosis in patients with T-cell malignancies. This study provides a theoretical basis for further elucidating the antitumor effects of disulfiram and the potential use of UBE2J1 as a biomarker for risk stratification in T-cell malignancies.
| [1] |
COOPER M L, DIPERSIO J F. Chimeric antigen receptor T cells (CAR-T) for the treatment of T-cell malignancies[J]. Best Pract Res Clin Haematol, 2019, 32(4): 101097. doi: 10.1016/j.beha.2019.101097.
|
| [2] |
CHEN C T, CHEN S H, LUO G X, et al. High expression of TMEM244 is associated with poor overall survival of patients with T-cell lymphoma[J]. Biomark Res, 2022, 10(1): 46. doi: 10.1186/s40364-022-00395-z.
|
| [3] |
LI K H, CHEN C T, GAO R L, et al. Inhibition of BCL11B induces downregulation of PTK7 and results in growth retardation and apoptosis in T-cell acute lymphoblastic leukemia[J]. Biomark Res, 2021, 9(1): 17. doi: 10.1186/s40364-021-00270-3.
|
| [4] |
BASSAN R, BOURQUIN J P, DEANGELO D J, et al. New approaches to the management of adult acute lymphoblastic leukemia[J]. J Clin Oncol, 2018, 36(35): 3504−3519. doi: 10.1200/JCO.2017.77.3648.
|
| [5] |
GRUNENBERG A, SALA E, KAPP-SCHWOERER S, et al. Pharmacotherapeutic management of T-cell acute lymphoblastic leukemia in adults: an update of the literature[J]. Expert Opin Pharmacother, 2022, 23(5): 561−571. doi: 10.1080/14656566.2022.2033725.
|
| [6] |
CHEN C T, NIE D R, HUANG Y X, et al. Anticancer effects of disulfiram in T-cell malignancies through NPL4-mediated ubiquitin-proteasome pathway[J]. J Leukoc Biol, 2022, 112(4): 919−929. doi: 10.1002/JLB.5MA1121-644R.
|
| [7] |
NIE D R, CHEN C T, LI Y Q, et al. Disulfiram, an aldehyde dehydrogenase inhibitor, works as a potent drug against sepsis and cancer via NETosis, pyroptosis, apoptosis, ferroptosis, and cuproptosis[J]. Blood Sci, 2022, 4(3): 152−154. doi: 10.1097/BS9.0000000000000117.
|
| [8] |
LU B S, YIN Y W, ZHANG Y P, et al. Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA[J]. Cancer Cell Int, 2019, 19: 149. doi: 10.1186/s12935-019-0874-2.
|
| [9] |
YOSHINO H, YAMADA Y, ENOKIDA H, et al. Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma[J]. PLoS One, 2020, 15(7): e0236119. doi: 10.1371/journal.pone.0236119.
|
| [10] |
IQBAL J, WRIGHT G, WANG C, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma[J]. Blood, 2014, 123(19): 2915−2923. doi: 10.1182/blood-2013-11-536359.
|
| [11] |
HAFERLACH T, KOHLMANN A, WIECZOREK L, et al. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the international microarray innovations in leukemia study group[J]. J Clin Oncol, 2010, 28(15): 2529−2537. doi: 10.1200/ JCO.2009.23.4732.
|
| [12] |
COUSTAN-SMITH E, SONG G C, CLARK C, et al. New markers for minimal residual disease detection in acute lymphoblastic leukemia[J]. Blood, 2011, 117(23): 6267−6276. doi: 10.1182/blood-2010-12-324004.
|
| [13] |
DING F B, XIAO H B, WANG M S, et al. The role of the ubiquitin-proteasome pathway in cancer development and treatment[J]. Front Biosci, 2014, 19(6): 886−895. doi: 10.2741/4254.
|
| [14] |
VAZ B, HALDER S, RAMADAN K. Role of p97/VCP (Cdc48) in genome stability[J]. Front Genet, 2013, 4: 60. doi: 10.3389/fgene.2013.00060.
|
| [15] |
BODNAR N O, KIM K H, JI Z J, et al. Structure of the Cdc48 ATPase with its ubiquitin-binding cofactor Ufd1-Npl4[J]. Nat Struct Mol Biol, 2018, 25(7): 616−622. doi: 10.1038/s41594-018-0085-x.
|
| [16] |
ISAACSON R L, PYE V E, SIMPSON P, et al. Detailed structural insights into the p97-Npl4-Ufd1 interface[J]. J Biol Chem, 2007, 282(29): 21361−21369. doi: 10.1074/jbc.M610069200.
|
| [17] |
Cancer Discovery Editorial Staff. The alcohol-abuse drug disulfiram targets NPL4 to exert antitumor effects[J]. Cancer Discov, 2018, 8(2): OF7. doi: 10.1158/2159-8290.CD-RW2017- 235.
|
| [18] |
SHARMA V, VERMA V, LAL N, et al. Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor β[J]. Mol Carcinog, 2016, 55(11): 1843−1857. doi: 10.1002/mc.22433.
|
| [19] |
ZHANG X, HU P, DING S Y, et al. Induction of autophagy-dependent apoptosis in cancer cells through activation of ER stress: an uncovered anti-cancer mechanism by anti-alcoholism drug disulfiram[J]. Am J Cancer Res, 2019, 9(6): 1266−1281.
|
| [20] |
HASSANI S, GHAFFARI P, CHAHARDOULI B, et al. Disulfiram/copper causes ROS levels alteration, cell cycle inhibition, and apoptosis in acute myeloid leukaemia cell lines with modulation in the expression of related genes[J]. Biomed Pharmacother, 2018, 99: 561−569. doi: 10.1016/j.biopha.2018.01.109.
|
| [21] |
WANG T, JIN C, YANG P, et al. UBE2J1 inhibits colorectal cancer progression by promoting ubiquitination and degradation of RPS3[J]. Oncogene, 2023, 42(9): 651−664. doi: 10.1038/s41388-022-02581-7.
|
| [22] |
WU C J, CONZE D B, LI X M, et al. TNF-α induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination[J]. EMBO J, 2005, 24(10): 1886−1898. doi: 10.1038/sj.emboj.7600649.
|
| [23] |
BURR M L, CANO F, SVOBODOVA S, et al. HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation[J]. Proc Natl Acad Sci USA, 2011, 108(5): 2034−2039. doi: 10.1073/pnas.1016229108.
|
| [24] |
YOUNGER J M, CHEN L L, REN H Y, et al. Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator[J]. Cell, 2006, 126(3): 571−582. doi: 10.1016/j.cell.2006.06.041.
|
| [25] |
FENG T T, DENG L, LU X C, et al. Ubiquitin-conjugating enzyme UBE2J1 negatively modulates interferon pathway and promotes RNA virus infection[J]. Virol J, 2018, 15(1): 132. doi: 10.1186/s12985-018-1040-5.
|
DownLoad: