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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

Deubiquitylase USP31 Induces Autophagy and Promotes the Progression in Lung Squamous Cell Carcinoma Cells by Stabilizing E2F1 Expression

Author(s): Wenjun Liang, Mingxia Yang, Xiaohua Wang, Yan Qian, Ruichen Gao, Yujia Shi, Xuejun Shi, Lei Shi, Ting Xu and Qian Zhang*

Volume 24, Issue 9, 2024

Published on: 08 January, 2024

Page: [975 - 986] Pages: 12

DOI: 10.2174/0115680096264557231124102054

Price: $65


Background: Autophagy exerts a vital role in the progression of lung squamous cell carcinoma (LUSC). Ubiquitin-specific peptidase 31 (USP31) has recently been found to be involved in the development of a variety of cancers. However, whether USP31 modulates autophagy in LUSC remains unclear.

Methods: This study revealed that high levels of USP31 were discovered in LUSC tissue samples employing the Gene Expression Profiling Interactive Analysis (GEPIA) database, quantitative real- time PCR (qRT-PCR), and Western blot analysis. Cell proliferation was tested via cell counting kit 8 (CCK-8) as well as colony formation, demonstrating that USP31-stable knockdown reduced cell viability.

Results: Immunofluorescence analysis illustrated that USP31 knockdown blocked the occurrence of LUSC autophagy. Meanwhile, USP31 has been shown to stabilize the expression of E2F transcription factor 1 (E2F1) through the proteasome pathway. Furthermore, overexpressed E2F1 effectively eliminated the effect of USP31 knockdown on LUSC cell proliferation and autophagy.

Conclusion: In summary, this investigation proved that USP31 promoted LUSC cell growth and autophagy, at least in part by stabilizing E2F1 expression, which provided a potential therapeutic gene for the treatment of LUSC.

Keywords: Lung squamous cell carcinoma, proliferation, ubiquitin specific peptidase 31, E2F transcription factor 1, lung cancer, NSCLC.

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Zhang, P.; Li, H.; Cheng, X.; Wang, W. Comprehensive analysis of immune cell infiltration of m6a-related lncRNA in lung squamous cell carcinoma and construction of relevant prognostic models. BioMed Res. Int., 2022, 2022, 1-25.
[] [PMID: 35872842]
Goldstraw, P.; Ball, D.; Jett, J.R.; Le Chevalier, T.; Lim, E.; Nicholson, A.G.; Shepherd, F.A. Non-small-cell lung cancer. Lancet, 2011, 378(9804), 1727-1740.
[] [PMID: 21565398]
Zhang, J.; Han, X.; Gao, C.; Xing, Y.; Qi, Z.; Liu, R.; Wang, Y.; Zhang, X.; Yang, Y.G.; Li, X.; Sun, B.; Tian, X. 5-hydroxymethylome in circulating cell-free dna as a potential biomarker for non-small-cell lung cancer. Genom. Proteom. Bioinform., 2018, 16(3), 187-199.
[] [PMID: 30010036]
Torre, L.A.; Siegel, R.L.; Jemal, A. Lung Cancer Statistics. Adv. Exp. Med. Biol., 2016, 893, 1-19.
[] [PMID: 26667336]
Wood, S.L.; Pernemalm, M.; Crosbie, P.A.; Whetton, A.D. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat. Rev., 2014, 40(4), 558-566.
[] [PMID: 24176790]
Rabinowitz, J.D.; White, E. Autophagy and metabolism. Science, 2010, 330(6009), 1344-1348.
[] [PMID: 21127245]
Mathew, R.; Karantza-Wadsworth, V.; White, E. Role of autophagy in cancer. Nat. Rev. Cancer, 2007, 7(12), 961-967.
[] [PMID: 17972889]
Bhutia, S.K.; Mukhopadhyay, S.; Sinha, N.; Das, D.N.; Panda, P.K.; Patra, S.K.; Maiti, T.K.; Mandal, M.; Dent, P.; Wang, X.Y.; Das, S.K.; Sarkar, D.; Fisher, P.B. Autophagy. Adv. Cancer Res., 2013, 118, 61-95.
[] [PMID: 23768510]
Yim, W.W.Y.; Mizushima, N. Lysosome biology in autophagy. Cell Discov., 2020, 6(1), 6.
[] [PMID: 32047650]
Nakamura, S.; Yoshimori, T. New insights into autophagosome-lysosome fusion. J. Cell Sci., 2017, 130(7), 1209-1216.
[PMID: 28302910]
Amaravadi, R.; Kimmelman, A.C.; White, E. Recent insights into the function of autophagy in cancer. Genes Dev., 2016, 30(17), 1913-1930.
[] [PMID: 27664235]
Amaravadi, R.K.; Kimmelman, A.C.; Debnath, J. Targeting autophagy in Cancer: Recent advances and future directions. Cancer Discov., 2019, 9(9), 1167-1181.
[] [PMID: 31434711]
Fan, Q.; Yang, L.; Zhang, X.; Ma, Y.; Li, Y.; Dong, L.; Zong, Z.; Hua, X.; Su, D.; Li, H.; Liu, J. Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β- catenin signaling pathway activation in hepatocellular carcinoma cells. J. Exp. Clin. Cancer Res., 2018, 37(1), 9.
[] [PMID: 29351758]
Marsh, T.; Debnath, J. Autophagy suppresses breast cancer metastasis by degrading NBR1. Autophagy, 2020, 16(6), 1164-1165.
[] [PMID: 32267786]
Yang, J.; Rao, S.; Cao, R.; Xiao, S.; Cui, X.; Ye, L. miR-30a-5p suppresses lung squamous cell carcinoma via ATG5 - mediated autophagy. Aging, 2021, 13(13), 17462-17472.
[] [PMID: 34253689]
Wang, J.; Xie, S.; Yang, J.; Xiong, H.; Jia, Y.; Zhou, Y.; Chen, Y.; Ying, X.; Chen, C.; Ye, C.; Wang, L.; Zhou, J. The long noncoding RNA H19 promotes tamoxifen resistance in breast cancer via autophagy. J. Hematol. Oncol., 2019, 12(1), 81.
[] [PMID: 31340867]
Reyes-Turcu, F.E.; Ventii, K.H.; Wilkinson, K.D. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu. Rev. Biochem., 2009, 78(1), 363-397.
[] [PMID: 19489724]
Tzimas, C.; Michailidou, G.; Arsenakis, M.; Kieff, E.; Mosialos, G.; Hatzivassiliou, E.G. Human ubiquitin specific protease 31 is a deubiquitinating enzyme implicated in activation of nuclear factor-κB. Cell. Signal., 2006, 18(1), 83-92.
[] [PMID: 16214042]
Qiao, X.; Zhang, Y.; Sun, L.; Ma, Q.; Yang, J.; Ai, L.; Xue, J.; Chen, G.; Zhang, H.; Ji, C.; Gu, X.; Lei, H.; Yang, Y.; Liu, C. Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis. eLife, 2021, 10, e65418.
[] [PMID: 34318746]
Ye, S.; Lawlor, M.A.; Rivera-Reyes, A.; Egolf, S.; Chor, S.; Pak, K.; Ciotti, G.E.; Lee, A.C.; Marino, G.E.; Shah, J.; Niedzwicki, D.; Weber, K.; Park, P.M.C.; Alam, M.Z.; Grazioli, A.; Haldar, M.; Xu, M.; Perry, J.A.; Qi, J.; Eisinger-Mathason, T.S.K. YAP1- mediated suppression of USP31 enhances NFκB activity to promote sarcomagenesis. Cancer Res., 2018, 78(10), 2705-2720.
[] [PMID: 29490948]
Hou, Y.; Fan, Y.; Xia, X.; Pan, J.; Hou, J.; Liu, X.; Chen, X. USP31 acetylation at Lys1264 is essential for its activity and cervical cancer cell growth. Acta Biochim. Biophys. Sin., 2021, 53(8), 1037-1043.
[] [PMID: 34184746]
Xiao, H.; Wu, Y.P.; Yang, C.C.; Yi, Z.; Zeng, N.; Xu, Y.; Zeng, H.; Deng, P.; Zhang, Q.; Wu, M. Knockout of E2F1 enhances the polarization of M2 phenotype macrophages to accelerate the wound healing process. Kaohsiung J. Med. Sci., 2020, 36(9), 692-698.
[] [PMID: 32349192]
Xiong, M.; Hu, W.; Tan, Y.; Yu, H.; Zhang, Q.; Zhao, C.; Yi, Y.; Wang, Y.; Wu, Y.; Wu, M. Transcription factor E2F1 knockout promotes mice white adipose tissue browning through autophagy inhibition. Front. Physiol., 2021, 12, 748040.
[] [PMID: 34819874]
Li, C.; Tang, Z.; Zhang, W.; Ye, Z.; Liu, F. GEPIA2021: integrating multiple deconvolution-based analysis into GEPIA. Nucleic Acids Res., 2021, 49(W1), W242-W246.
[] [PMID: 34050758]
Li, X.; Yang, K.B.; Chen, W.; Mai, J.; Wu, X.Q.; Sun, T.; Wu, R.Y.; Jiao, L.; Li, D.D.; Ji, J.; Zhang, H.L.; Yu, Y.; Chen, Y.H.; Feng, G.K.; Deng, R.; Li, J.D.; Zhu, X.F. CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression. Autophagy, 2021, 17(12), 4323-4340.
[] [PMID: 33977871]
Feng, X.; Zhang, H.; Meng, L.; Song, H.; Zhou, Q.; Qu, C.; Zhao, P.; Li, Q.; Zou, C.; Liu, X.; Zhang, Z. Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5. Autophagy, 2021, 17(3), 723-742.
[] [PMID: 32186433]
Tanaka, T.; Warner, B.M.; Michael, D.G.; Nakamura, H.; Odani, T.; Yin, H.; Atsumi, T.; Noguchi, M.; Chiorini, J.A. LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization. Autophagy, 2022, 18(7), 1629-1647.
[] [PMID: 34802379]
Wang, L.; Yang, J.; Wang, H.; Fu, R.; Liu, X.; Piao, Y.; Wei, L.; Wang, J.; Zhang, L. LncRNA BCYRN1-induced autophagy enhances asparaginase resistance in extranodal NK/T-cell lymphoma. Theranostics, 2021, 11(2), 925-940.
[] [PMID: 33391513]
Dai, X.; Lu, L.; Deng, S.; Meng, J.; Wan, C.; Huang, J.; Sun, Y.; Hu, Y.; Wu, B.; Wu, G.; Lovell, J.F.; Jin, H.; Yang, K. USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer. Theranostics, 2020, 10(20), 9332-9347.
[] [PMID: 32802195]
He, Y.; Jiang, S.; Mao, C.; Zheng, H.; Cao, B.; Zhang, Z.; Zhao, J.; Zeng, Y.; Mao, X. The deubiquitinase USP10 restores PTEN activity and inhibits non–small cell lung cancer cell proliferation. J. Biol. Chem., 2021, 297(3), 101088.
[] [PMID: 34416231]
Cai, J.; Li, M.; Wang, X.; Li, L.; Li, Q.; Hou, Z.; Jia, H.; Liu, S. USP37 promotes lung cancer cell migration by stabilizing snail protein via deubiquitination. Front. Genet., 2020, 10, 1324.
[] [PMID: 31998374]
Sun, Q.; Zhang, J.; Li, X.; Yang, G.; Cheng, S.; Guo, D.; Zhang, Q.; Sun, F.; Zhao, F.; Yang, D.; Wang, S.; Wang, T.; Liu, S.; Zou, L.; Zhang, Y.; Liu, H. The ubiquitin-specific protease 8 antagonizes melatonin-induced endocytic degradation of MT1 receptor to promote lung adenocarcinoma growth. J. Adv. Res., 2022, 41, 1-12.
[] [PMID: 36328739]
Huang, Y.; Jiang, P.; Chen, Y.; Wang, J.; Yuan, R. Systemic analysis of the expression and prognostic significance of USP31 in endometrial cancer. Bosn. J. Basic Med. Sci., 2022.
Sridhar, S.; Botbol, Y.; Macian, F.; Cuervo, A.M. Autophagy and disease: Always two sides to a problem. J. Pathol., 2012, 226(2), 255-273.
[] [PMID: 21990109]
Mah, L.Y.; Ryan, K.M. Autophagy and cancer. Cold Spring Harb. Perspect. Biol., 2012, 4(1), a008821.
[] [PMID: 22166310]
Poillet-Perez, L.; White, E. Role of tumor and host autophagy in cancer metabolism. Genes Dev., 2019, 33(11-12), 610-619.
[] [PMID: 31160394]
Barnard, R.A.; Regan, D.P.; Hansen, R.J.; Maycotte, P.; Thorburn, A.; Gustafson, D.L. Autophagy inhibition delays early but not late-stage metastatic disease. J. Pharmacol. Exp. Ther., 2016, 358(2), 282-293.
[] [PMID: 27231155]
Wu, W.K.K.; Coffelt, S.B.; Cho, C.H.; Wang, X.J.; Lee, C.W.; Chan, F.K.L.; Yu, J.; Sung, J.J.Y. The autophagic paradox in cancer therapy. Oncogene, 2012, 31(8), 939-953.
[] [PMID: 21765470]
Guo, J.Y.; Xia, B.; White, E. Autophagy-mediated tumor promotion. Cell, 2013, 155(6), 1216-1219.
[] [PMID: 24315093]
Li, H.; Roy, M.; Liang, L.; Cao, W.; Hu, B.; Li, Y.; Xiao, X.; Wang, H.; Ye, M.; Sun, S.; Zhang, B.; Liu, J. Deubiquitylase USP12 induces pro-survival autophagy and bortezomib resistance in multiple myeloma by stabilizing HMGB1. Oncogene, 2022, 41(9), 1298-1308.
[] [PMID: 34997217]
Niu, K.; Fang, H.; Chen, Z.; Zhu, Y.; Tan, Q.; Wei, D.; Li, Y.; Balajee, A.S.; Zhao, Y. USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy. Autophagy, 2020, 16(4), 724-734.
[] [PMID: 31432739]
Sharma, A.; Alswillah, T.; Singh, K.; Chatterjee, P.; Willard, B.; Venere, M.; Summers, M.K.; Almasan, A. USP14 regulates DNA damage repair by targeting RNF168-dependent ubiquitination. Autophagy, 2018, 14(11), 1976-1990.
[] [PMID: 29995557]
Zheng, X.; Huang, M.; Xing, L.; Yang, R.; Wang, X.; Jiang, R.; Zhang, L.; Chen, J. The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer. Mol. Cancer, 2020, 19(1), 73.
[] [PMID: 32264877]
Stanelle, J.; Pützer, B.M. E2F1-induced apoptosis: Turning killers into therapeutics. Trends Mol. Med., 2006, 12(4), 177-185.
[] [PMID: 16530485]
Liu, H.; Lu, Z.; Shi, X.; Liu, L.; Zhang, P.; Golemis, E.A.; Tu, Z. HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression. J. Biol. Chem., 2021, 297(2), 100996.
[] [PMID: 34302809]
Ropolo, A.; Catrinacio, C.; Renna, F.J.; Boggio, V.; Orquera, T.; Gonzalez, C.D.; Vaccaro, M.I. A novel E2F1-EP300-VMP1 pathway mediates gemcitabine-induced autophagy in pancreatic cancer cells carrying oncogenic KRAS. Front. Endocrinol., 2020, 11, 411.
[] [PMID: 32655498]
Xin, R.; Hu, B.; Qu, D.; Chen, D. WITHDRAWN: Oncogenic lncRNA MALAT-1 recruits E2F1 to upregulate RAD51 expression and thus promotes cell autophagy and tumor growth in non-small cell lung cancer. Pulm Pharmacol Ther , 2023, 102199.
[] [PMID: 36690318]

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