Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2020

Open Access 01-12-2020 | Primary research

Ubiquitin ligase CHAF1B induces cisplatin resistance in lung adenocarcinoma by promoting NCOR2 degradation

Authors: Lian Gong, Yi Hu, Dong He, Yuxing Zhu, Liang Xiang, Mengqing Xiao, Ying Bao, Xiaoming Liu, Qinghai Zeng, Jianye Liu, Ming Zhou, Yanhong Zhou, Yaxin Cheng, Yeyu Zhang, Liping Deng, Rongrong Zhu, Hua Lan, Ke Cao

Published in: Cancer Cell International | Issue 1/2020

Login to get access

Abstract

Background

Lung cancer is the most common malignant tumor in the world. The Whole-proteome microarray showed that ubiquitin ligase chromatin assembly factor 1 subunit B (CHAF1B) expression in A549/DDP cells is higher than in A549 cells. Our study explored the molecular mechanism of CHAF1B affecting cisplatin resistance in lung adenocarcinoma (LUAD).

Methods

Proteome microarray quantify the differentially expressed proteins between LUAD cell line A549 and its cisplatin-resistant strain A549/DDP. Quantitative real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot (WB) confirmed the CHAF1B expression. Public databases analyzed the prognosis of LUAD patients with varied LUAD expression followed by the substrates prediction of CHAF1B. Public databases showed that nuclear receptor corepressor 2 (NCOR2) may be substrates of CHAF1B. WB detected that CHAF1B expression affected the expression of NCOR2. Cell and animal experiments and clinical data detected function and integrating mechanism of CHAF1B compounds.

Results

Proteome chips results indicated that CHAF1B, PPP1R13L, and CDC20 was higher than A549 in A549/DDP. Public databases showed that high expression of CHAF1B, PPP1R13L, and CDC20 was negatively correlated with prognosis in LUAD patients. PCR and WB results indicated higher CHAF1B expression in A549/DDP cells than that in A549 cells. NCOR2 and PPP5C were confirmed to be substrates of CHAF1B. CHAF1B knockdown significantly increased the sensitivity of cisplatin in A549/DDP cells and the upregulated NCOR2 expression. CHAF1B and NCOR2 are interacting proteins and the position of interaction between CHAF1B and NCOR2 was mainly in the nucleus. CHAF1B promotes ubiquitination degradation of NCOR2. Cells and animal experiments showed that under the action of cisplatin, after knockdown of CHAF1B and NCOR2 in A549/DDP group compared with CHAF1B knockdown alone, the cell proliferation and migratory ability increased and apoptotic rate decreased, and the growth rate and size of transplanted tumor increased significantly. Immunohistochemistry suggested that Ki-67 increased, while apoptosis-related indicators caspase-3 decreased significantly. Clinical data showed that patients with high expression of CHAF1B are more susceptible to cisplatin resistance.

Conclusion

Ubiquitin ligase CAHF1B can induce cisplatin resistance in LUAD by promoting the ubiquitination degradation of NCOR2.
Appendix
Available only for authorised users
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.PubMed
2.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.PubMedCrossRef
3.
Amable L. Cisplatin resistance and opportunities for precision medicine. Pharmacol Res. 2016;106:27–36.PubMedCrossRef
4.
Zhu H, Luo H, Zhang W, Shen Z, Hu X, Zhu X. Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des Dev Ther. 2016;10:1885–18995.CrossRef
5.
Wang L, Liu X, Ren Y, Zhang J, Chen J, Zhou W, Guo W, Wang X, Chen H, Li M, et al. Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity. Cell Death Dis. 2017;8(4):e2746.PubMedPubMedCentralCrossRef
6.
Feng X, Liu H, Zhang Z, Gu Y, Qiu H, He Z. Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells. J Exp Clin Cancer Res. 2017;36(1):123.PubMedPubMedCentralCrossRef
7.
Lai YH, Kuo C, Kuo MT, Chen HHW. Modulating chemosensitivity of tumors to platinum-based antitumor drugs by transcriptional regulation of copper homeostasis. Int J Mol Sci. 2018;19(5):1486.PubMedCentralCrossRef
8.
Liu X, Xu Y, Pang Z, Guo F, Qin Q, Yin T, Sang Y, Feng C, Li X, Jiang L, et al. Knockdown of SUMO-activating enzyme subunit 2 (SAE2) suppresses cancer malignancy and enhances chemotherapy sensitivity in small cell lung cancer. J Hematol Oncol. 2015;8:67.PubMedPubMedCentralCrossRef
9.
Flem-Karlsen K, Tekle C, Oyjord T, Florenes VA, Maelandsmo GM, Fodstad O, Nunes-Xavier CE. p38 MAPK activation through B7-H3-mediated DUSP10 repression promotes chemoresistance. Sci Rep. 2019;9(1):5839.PubMedPubMedCentralCrossRef
10.
Yang M, Qu Y, Shi R, Wu X, Su C, Hu Z, Chang Q, Liu S, Pan G, Lei M, et al. Ubiquitin-conjugating enzyme UbcH10 promotes gastric cancer growth and is a potential biomarker for gastric cancer. Oncol Rep. 2016;36(2):779–86.PubMedCrossRef
11.
Hildebrandt A, Bruggemann M, Ruckle C, Boerner S, Heidelberger JB, Busch A, Hanel H, Voigt A, Mockel MM, Ebersberger S, et al. The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation. Genome Biol. 2019;20(1):216.PubMedPubMedCentralCrossRef
12.
Guillamot M, Ouazia D, Dolgalev I, Yeung ST, Kourtis N, Dai Y, Corrigan K, Zea-Redondo L, Saraf A, Florens L, et al. The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MYD88 degradation. Nat Immunol. 2019;20(9):1196–207.PubMedCrossRefPubMedCentral
13.
Lu G, Yi J, Gubas A, Wang YT, Wu Y, Ren Y, Wu M, Shi Y, Ouyang C, Tan HWS, et al. Suppression of autophagy during mitosis via CUL4-RING ubiquitin ligases-mediated WIPI2 polyubiquitination and proteasomal degradation. Autophagy. 2019;15(11):1917–34.PubMedPubMedCentralCrossRef
14.
Zacharioudakis E, Agarwal P, Bartoli A, Abell N, Kunalingam L, Bergoglio V, Xhemalce B, Miller KM, Rodriguez R. Chromatin Regulates Genome Targeting with Cisplatin. Angew Chem Int Ed Engl. 2017;56(23):6483–7.PubMedPubMedCentralCrossRef
15.
MacKay C, Carroll E, Ibrahim AFM, Garg A, Inman GJ, Hay RT, Alpi AF. E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin. Cancer Res. 2014;74(8):2246–57.PubMedPubMedCentralCrossRef
16.
Liu Z, Wu Y, Tao Z, Ma L. E3 ubiquitin ligase Hakai regulates cell growth and invasion, and increases the chemosensitivity to cisplatin in non-small cell lung cancer cells. Int J Mol Med. 2018;42(2):1145–51.PubMed
17.
Campbell AE, Shadle SC, Jagannathan S, Lim JW, Resnick R, Tawil R, van der Maarel SM, Tapscott SJ. NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins. Elife. 2018;7:e31023.PubMedPubMedCentralCrossRef
18.
Jia L, Li B, Yu H. The Bub1-Plk1 kinase complex promotes spindle checkpoint signalling through Cdc20 phosphorylation. Nat Commun. 2016;7:1–14.
19.
Chen Y, Yan W, He S, Chen J, Chen D, Zhang Z, Liu Z, Ding X, Wang A. In vitro effect of iASPP on cell growth of oral tongue squamous cell carcinoma. Chin J Cancer Res. 2014;26(4):382–90.PubMedPubMedCentral
20.
Wang J, Zhang Y, Dou Z, Jiang H, Wang Y, Gao X, Xin X. Knockdown of STIL suppresses the progression of gastric cancer by down-regulating the IGF-1/PI3K/AKT pathway. J Cell Mol Med. 2019;23(8):5566–75.PubMedPubMedCentralCrossRef
21.
Wu B, Liu ZY, Cui J, Yang XM, Jing L, Zhou Y, Chen ZN, Jiang JL. F-Box protein FBXO22 mediates polyubiquitination and degradation of cd147 to reverse cisplatin resistance of tumor cells. Int J Mol Sci. 2017;18(1):212.PubMedCentralCrossRef
22.
Wang L, Arras J, Katsha A, Hamdan S, Belkhiri A, Ecsedy J, El-Rifai W. Cisplatin-resistant cancer cells are sensitive to Aurora kinase A inhibition by alisertib. Mol Oncol. 2017;11(8):981–95.PubMedPubMedCentralCrossRef
23.
Xiong Y, Sun F, Dong P, Watari H, Yue J, Yu MF, Lan CY, Wang Y, Ma ZB. iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling. J Exp Clin Cancer Res. 2017;36(1):48.PubMedPubMedCentralCrossRef
24.
Kaufman PD, Kobayashi R, Kessler N, Stillman B. The p150 and p60 subunits of chromatin assembly factor I: a molecular link between newly synthesized histones and DNA replication. Cell. 1995;81(7):1105–14.PubMedCrossRef
25.
Martini E, Roche DM, Marheineke K, Verreault A, Almouzni G. Recruitment of phosphorylated chromatin assembly factor 1 to chromatin after UV irradiation of human cells. J Cell Biol. 1998;143(3):563–75.PubMedPubMedCentralCrossRef
26.
Mascolo M, Ilardi G, Merolla F, Russo D, Vecchione ML, de Rosa G, Staibano S. Tissue microarray-based evaluation of Chromatin Assembly Factor-1 (CAF-1)/p60 as tumour prognostic marker. Int J Mol Sci. 2012;13(9):11044–62.PubMedPubMedCentralCrossRef
27.
de Tayrac M, Saikali S, Aubry M, Bellaud P, Boniface R, Quillien V, Mosser J. Prognostic significance of EDN/RB, HJURP, p60/CAF-1 and PDLI4, four new markers in high-grade gliomas. PLoS ONE. 2013;8(9):e73332.PubMedPubMedCentralCrossRef
28.
Staibano S, Mascolo M, Mancini FP, Kisslinger A, Salvatore G, Di Benedetto M, Chieffi P, Altieri V, Prezioso D, Ilardi G, et al. Overexpression of chromatin assembly factor-1 (CAF-1) p60 is predictive of adverse behaviour of prostatic cancer. Histopathology. 2009;54(5):580–9.PubMedCrossRef
29.
Duan Y, Liu T, Li S, Huang M, Li X, Zhao H, Li J. CHAF1B promotes proliferation and reduces apoptosis in 95D lung cancer cells and predicts a poor prognosis in non-small cell lung cancer. Oncol Rep. 2019;41(4):2518–28.PubMed
30.
Peng X, Fu H, Yin J, Zhao Q. CHAF1B knockdown blocks migration in a hepatocellular carcinoma model. Oncol Rep. 2018;40(1):405–13.PubMed
31.
Staibano S, Mascolo M, Rocco A, Lo Muzio L, Ilardi G, Siano M, Pannone G, Vecchione ML, Nugnes L, Califano L, et al. The proliferation marker Chromatin Assembly Factor-1 is of clinical value in predicting the biological behaviour of salivary gland tumours. Oncol Rep. 2011;25(1):13–22.PubMed
32.
Cui J, Yang Y, Zhang C, Hu P, Kan W, Bai X, Liu X, Song H. FBI-1 functions as a novel AR co-repressor in prostate cancer cells. Cell Mol Life Sci. 2011;68(6):1091–103.PubMedCrossRef
33.
Alam H, Li N, Dhar SS, Wu SJ, Lv J, Chen K, Flores ER, Baseler L, Lee MG. HP1gamma promotes lung adenocarcinoma by downregulating the transcription-repressive regulators NCOR2 and ZBTB7A. Cancer Res. 2018;78(14):3834–48.PubMedPubMedCentralCrossRef
34.
Martinez-Iglesias OA, Alonso-Merino E, Gomez-Rey S, Velasco-Martin JP, Martin Orozco R, Luengo E, Garcia Martin R, de Ibanez Caceres I, Fernandez AF, Fraga MF, et al. Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis. Proc Natl Acad Sci USA. 2016;113(3):E328–37.PubMedCrossRefPubMedCentral
Metadata
Title
Ubiquitin ligase CHAF1B induces cisplatin resistance in lung adenocarcinoma by promoting NCOR2 degradation
Authors
Lian Gong
Yi Hu
Dong He
Yuxing Zhu
Liang Xiang
Mengqing Xiao
Ying Bao
Xiaoming Liu
Qinghai Zeng
Jianye Liu
Ming Zhou
Yanhong Zhou
Yaxin Cheng
Yeyu Zhang
Liping Deng
Rongrong Zhu
Hua Lan
Ke Cao
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01263-2

Other articles of this Issue 1/2020

Cancer Cell International 1/2020 Go to the issue

Primary research

LncRNA IGBP1-AS1/miR-24-1/ZIC3 loop regulates the proliferation and invasion ability in breast cancer

Primary research

Long noncoding RNA SNHG4 promotes renal cell carcinoma tumorigenesis and invasion by acting as ceRNA to sponge miR-204-5p and upregulate RUNX2

Primary research

Activation of the LINC00242/miR-141/FOXC1 axis underpins the development of gastric cancer

Primary research

Exosomal miR-126 blocks the development of non-small cell lung cancer through the inhibition of ITGA6

Primary research

LncRNA MEG3 promotes melanoma growth, metastasis and formation through modulating miR-21/E-cadherin axis

Primary research

A methylation‐based mRNA signature predicts survival in patients with gastric cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits