- Personal Center
- Logout
FOLLOWUS
- Current Issue
- Current Issue
- Latest Articles
- Archive
- Special Issues
N 6-methyladenosine modification ofCENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance- Military Medical Research Vol. 9, Issue 5, Pages: 576-591(2022)
- Affiliations：
1.Departments of Gynecology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fujian Medical University, Fuzhou 350014, China
2.Department of Radiation Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fujian Medical University, Fuzhou 350014, China
3.Shenzhen Key Laboratory of Immunity and Inflammatory Diseases, Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong, China
4.Outpatient Department, Fujian Hospital of People’s Armed Police, Fujian Medical University, Fuzhou 350014, China
- Author bio：
* ccb@fjmu.edu.cn;
xuqinfj@163.com
- Funds：
DOI：10.1186/s40779-022-00378-z
CLC：-
Published：2022-10
- Accepted：
Scan QR Code
Lin X, Wang F, Chen J, Liu J, Lin YB, Li L, et al. N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance. Mil Med Res. 2022;9(1):19.
Lin X, Wang F, Chen J, Liu J, Lin YB, Li L, et al. N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance. Mil Med Res. 2022;9(1):19. DOI： 10.1186/s40779-022-00378-z.
摘要
Abstract
Background:
2
Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis. In the current study
we determined the relevant players and role of
N
6
-methyladenine (m
6
A) RNA methylation in cervical cancer progression.
Methods:
2
The roles of m
6
A RNA methylation and centromere protein K (CENPK) in cervical cancer were analyzed using bioinformatics analysis. Methylated RNA immunoprecipitation was adopted to detect m
6
A modification of
CENPK
mRNA. Human cervical cancer clinical samples
cell lines
and xenografts were used for analyzing gene expression and function. Immunofluorescence staining and the tumorsphere formation
clonogenic
MTT
and EdU assays were performed to determine cell stemness
chemoresistance
migration
invasion
and proliferation in HeLa and SiHa cells
respectively. Western blotting analysis
co-immunoprecipitation
chromatin immunoprecipitation
and luciferase reporter
cycloheximide chase
and cell fractionation assays were performed to elucidate the underlying mechanism.
Results:
2
Bioinformatics analysis of public cancer datasets revealed firm links between m
6
A modification patterns and cervical cancer prognosis
especially through ZC3H13-mediated m
6
A modification of
CENPK
mRNA. CENPK expression was elevated in cervical cancer
associated with cancer recurrence
and independently predicts poor patient prognosis [hazard ratio=1.413
95% confidence interval=1.078–1.853
P
=0.012]. Silencing of
CENPK
prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy
in vivo
(
P
<
0.001). We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK with β-catenin
which promoted β-catenin expression and nuclear translocation
facilitated p53 ubiquitination
and led to activation of Wnt/β-catenin signaling
but suppression of the p53 pathway. This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness
DNA damage repair pathways necessary for cisplatin/carboplatin resistance
epithelial-mesenchymal transition involved in metastasis
and DNA replication that drove tumor cell proliferation.
Conclusions:
2
CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.
关键词
Keywords
references
Sung H , Ferlay J , Siegel RL . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin . 2021 ; 71 ( 3 ): 209 - 49 .
Siegel RL , Miller KD , Fuchs HE , Jemal A . Cancer statistics, 2021 . CA Cancer J Clin . 2021 ; 71 ( 1 ): 7 - 33 .
He Y , Xiao M , Fu H , Chen L , Qi L , Liu D , et al . cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer . Stem Cells . 2020 ; 38 ( 4 ): 487 - 503 .
Wang H , Luo Q , Kang J , Wei Q , Yang Y , Yang D , et al . YTHDF1 aggravates the progression of cervical cancer through m 6 A-Mediated up-regulation of RANBP2 . Front Oncol . 2021 ; 11 : 650383 .
Li Z , Peng Y , Li J , Chen Z , Chen F , Tu J , et al . N 6 -methyladenosine regulates glycolysis of cancer cells through PDK4 . Nat Commun . 2020 ; 11 ( 1 ): 2578 .
Wang Q , Guo X , Li L , Gao Z , Su X , Ji M , et al . N 6 -methyladenosine METTL3 promotes cervical cancer tumorigenesis and Warburg effect through YTHDF1/HK2 modification . Cell Death Dis . 2020 ; 11 ( 10 ): 911 .
Zhao H , Xu Y , Xie Y , Zhang L , Gao M , Li S , et al . m 6 A regulators is differently expressed and correlated with immune response of esophageal cancer . Front Cell Dev Biol . 2021 ; 9 : 650023 .
Zhao Y , Shi Y , Shen H , Xie W . m 6 A-binding proteins: the emerging crucial performers in epigenetics . J Hematol Oncol . 2020 ; 13 ( 1 ): 35 .
Lee YC , Huang CC , Lin DY , Chang WC , Lee KH . Overexpression of centromere protein K (CENPK) in ovarian cancer is correlated with poor patient survival and associated with predictive and prognostic relevance . PeerJ . 2015 ; 3 : e1386 .
Komatsu M , Yoshimaru T , Matsuo T , Kiyotani K , Miyoshi Y , Tanahashi T , et al . Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis . Int J Oncol . 2013 ; 42 ( 2 ): 478 - 506 .
Wang H , Liu W , Liu L , Wu C , Wu W , Zheng J , et al . Overexpression of centromere protein K (CENP-K) gene in hepatocellular carcinoma promote cell proliferation by activating AKT/TP53 signal pathway . Oncotarget . 2017 ; 8 ( 43 ): 73994 - 4005 .
Liu Y , Xiong S , Liu S , Chen J , Yang H , Liu G , et al . Analysis of gene expression in bladder cancer: possible involvement of mitosis and complement and coagulation cascades signaling pathway . J Comput Biol . 2020 ; 27 ( 6 ): 987 - 98 .
Liu Y , Hu H , Zhang C , Wang H , Zhang W , Wang Z , et al . Co-expression of mitosis-regulating genes contributes to malignant progression and prognosis in oligodendrogliomas . Oncotarget . 2015 ; 6 ( 35 ): 38257 - 69 .
Ma J , Chen X , Lin M , Wang Z , Wu Y , Li J . Bioinformatics analysis combined with experiments predicts CENPK as a potential prognostic factor for lung adenocarcinoma . Cancer Cell Int . 2021 ; 21 ( 1 ): 65 .
Okada M , Cheeseman IM , Hori T , Okawa K , McLeod IX , Yates JRR , et al . The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres . Nat Cell Biol . 2006 ; 8 ( 5 ): 446 - 57 .
Zou Y , Lin X , Bu J , Lin Z , Chen Y , Qiu Y , et al . Timeless-stimulated miR-5188-FOXO1/β-catenin-c-Jun feedback loop promotes stemness via ubiquitination of β-catenin in breast cancer . Mol Ther . 2020 ; 28 ( 1 ): 313 - 27 .
Koivusalo R , Krausz E , Ruotsalainen P , Helenius H , Hietanen S . Chemoradiation of cervical cancer cells: targeting human papillomavirus E6 and p53 leads to either augmented or attenuated apoptosis depending on the platinum carrier ligand . Cancer Res . 2002 ; 62 ( 24 ): 7364 - 71 .
Zhou F , Yang X , Zhao H , Liu Y , Feng Y , An R , et al . Down-regulation of OGT promotes cisplatin resistance by inducing autophagy in ovarian cancer . Theranostics . 2018 ; 8 ( 19 ): 5200 - 12 .
Segovia-Mendoza M , Jurado R , Mir R , Medina LA , Prado-Garcia H , Garcia-Lopez P . Antihormonal agents as a strategy to improve the effect of chemo-radiation in cervical cancer: in vitro and in vivo study . BMC Cancer . 2015 ; 15 : 21 .
Mukherjee A , Chiang CY , Daifotis HA . Adipocyte-induced FABP4 expression in ovarian cancer cells promotes metastasis and mediates carboplatin resistance . Cancer Res . 2020 ; 80 ( 8 ): 1748 - 61 .
Lin X , Zuo S , Luo R , Li Y , Yu G , Zou Y , et al . HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma . Theranostics . 2019 ; 9 ( 25 ): 7583 - 98 .
Lin X , Li AM , Li YH , Luo RC , Zou YJ , Liu YY , et al . Silencing MYH9 blocks HBx-induced GSK3β ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma . Signal Transduct Target Ther . 2020 ; 5 ( 1 ): 13 .
Xu Q , Chen C , Liu B , Lin Y , Zheng P , Zhou D , et al . Association of iRhom1 and iRhom2 expression with prognosis in patients with cervical cancer and possible signaling pathways . Oncol Rep . 2020 ; 43 ( 1 ): 41 - 54 .
Lin X , Zheng X , Yang B , Chen J , Xu Q , Wang Q . Clinical significance and immune landscapes of stemness-related and immune gene set-based signature in oral cancer . Clin Transl Med . 2021 ; 11 ( 2 ): e343 .
Zhang B , Wu Q , Li B , Wang D , Wang L , Zhou YL . m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer . Mol Cancer . 2020 ; 19 ( 1 ): 53 .
Kitahara O , Katagiri T , Tsunoda T , Harima Y , Nakamura Y . Classification of sensitivity or resistance of cervical cancers to ionizing radiation according to expression profiles of 62 genes selected by cDNA microarray analysis . Neoplasia . 2002 ; 4 ( 4 ): 295 - 303 .
Dong P , Xiong Y , Yu J , Chen L , Tao T , Yi S , et al . Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4-miR-18a pathway in cervical cancer . Oncogene . 2018 ; 37 ( 39 ): 5257 - 68 .
Wang J , Ding S , Duan Z , Xie Q , Zhang T , Zhang X , et al . Role of p14ARFHDM2-p53 axis in SOX6-mediated tumor suppression . Oncogene . 2016 ; 35 ( 13 ): 1692 - 702 .
Budhwani M , Lukowski SW , Porceddu SV , Frazer IH , Chandra J . Dysregulation of stemness pathways in HPV mediated cervical malignant transformation identifies potential oncotherapy targets . Front Cell Infect Microbiol . 2020 ; 10 : 307 .
Lee SW , Lee SH , Kim J , Kim YS , Yoon MS , Jeong S , et al . Magnetic resonance imaging during definitive chemoradiotherapy can predict tumor recurrence and patient survival in locally advanced cervical cancer: a multi-institutional retrospective analysis of KROG 16–01 . Gynecol Oncol . 2017 ; 147 ( 2 ): 334 - 9 .
Li B , Jiang J , Assaraf YG , Xiao H , Chen ZS , Huang C . Surmounting cancer drug resistance: new insights from the perspective of N6-methyladenosine RNA modification . Drug Resist Updat . 2020 ; 53 : 100720 .
Wen J , Lv R , Ma H , Shen H , He C , Wang J , et al . Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal . Mol Cell . 2018 ; 69 ( 6 ): 1028 - 38 .
Pan J , Xu L , Pan H . Development and validation of an m6A RNA methylation regulator-based signature for prognostic prediction in cervical squamous cell carcinoma . Front Oncol . 2020 ; 10 : 1444 .
Knuckles P , Lence T , Haussmann IU , Jacob D , Kreim N , Carl SH , et al . Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d . Genes Dev . 2018 ; 32 ( 5–6 ): 415 - 29 .
Jiang W , Yuan Q , Jiang Y , Huang L , Chen C , Hu G , et al . Identification of Sox6 as a regulator of pancreatic cancer development . J Cell Mol Med . 2018 ; 22 ( 3 ): 1864 - 72 .
Liang Z , Xu J , Gu C . Novel role of the SRY-related high-mobility-group box D gene in cancer . Semin Cancer Biol . 2020 ; 67 ( Pt 1 ): 83 - 90 .
Lin M , Lei T , Zheng J , Chen S , Du L , Xie H . UBE2S mediates tumor progression via SOX6/β-Catenin signaling in endometrial cancer . Int J Biochem Cell Biol . 2019 ; 109 : 17 - 22 .
Chen Y , Song Y , Mi Y , Jin H , Cao J , Li H , et al . microRNA-499a promotes the progression and chemoresistance of cervical cancer cells by targeting SOX6 . Apoptosis . 2020 ; 25 ( 3–4 ): 205 - 16 .
Chen L , Xie Y , Ma X , Zhang Y , Li X , Zhang F , et al . SOX6 represses tumor growth of clear cell renal cell carcinoma by HMG domain-dependent regulation of Wnt/β-catenin signaling . Mol Carcinog . 2020 ; 59 ( 10 ): 1159 - 73 .
Kurtsdotter I , Topcic D , Karlén A , Singla B , Hagey DW , Bergsland M , et al . SOX5/6/21 prevent oncogene-driven transformation of brain stem cells . Cancer Res . 2017 ; 77 ( 18 ): 4985 - 97 .
He Y , Davies CM , Harrington BS , Hellmers L , Sheng Y . CDCP1 enhances Wnt signaling in colorectal cancer promoting nuclear localization of β-catenin and E-cadherin . Oncogene . 2020 ; 39 ( 1 ): 219 - 33 .
Hu C , Zhang M , Moses N , Hu CL , Polin L , Chen W , et al . The USP10-HDAC6 axis confers cisplatin resistance in non-small cell lung cancer lacking wild-type p53 . Cell Death Dis . 2020 ; 11 ( 5 ): 328 .
Zhong Z , Virshup DM . Wnt signaling and drug resistance in cancer . Mol Pharmacol . 2020 ; 97 ( 2 ): 72 - 89 .
Yu C , Chen F , Wang X , Cai Z , Yang M , Zhong Q , et al . Pin2 telomeric repeat factor 1-interacting telomerase inhibitor 1 (PinX1) inhibits nasopharyngeal cancer cell stemness: implication for cancer progression and therapeutic targeting . J Exp Clin Cancer Res . 2020 ; 39 ( 1 ): 31 .
0
Views
0
Downloads
0
CSCD
- L-PDFDownload
- Meta-XMLDownload
- BibTeXDownload
- EndnoteDownload
- RefMan Download
- NoteExpressDownload
- NoteFirstDownload
Publicity Resources
Related Articles
Related Author
Related Institution
- Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19
京公网安备11010802024621 - It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
- Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.