Identification of CDKL3 As a Critical Regulator in Development of Glioma Through Regulating RRM2 and the JNK Signaling Pathway

Overview

Journal Cancer Sci

Specialty Oncology

Date 2021 Jun 7

PMID 34097336

Citations 5

Authors

Yong Cui

Zhigang Yang

Hongxiang Wang

Yong Yan

Qilin Huang

Zhenyu Gong

Fan Hong

Xu Zhang

Weiqing Li

Juxiang Chen

Tao Xu

Affiliations

Soon will be listed here.

Abstract

Glioma is one of the most commonly diagnosed intracranial malignancies. The molecular mechanism underlying the development of glioma is still largely unknown. In this study, we present the first report concerning the function and mechanism of cyclin-dependent kinase-like 3 (CDKL3) in the development and prognosis of glioma. It is shown that CDKL3 was upregulated in glioma tissues and could independently predict poor prognosis of patients. Silencing CDKL3 in glioma cells could inhibit cell proliferation and migration and induce cell apoptosis and cell cycle arrest, whereas the overexpression of CDKL3 promoted cell proliferation. The in vivo experiments also indicated that knockdown of CDKL3 significantly suppressed tumor growth of glioma. Gene expression profiling of CDKL3 knockdown U87 cells identified RRM2 as a potential target of CDKL3, which was proved to have direct interaction with CDKL3. Given similar effects on glioma development with CDKL3, knockdown of RRM2 could rescue the effects of CDKL3 overexpression on glioma cells. Moreover, knockdown of CDKL3 or RRM2 suppressed the activity of JNK signaling, whereas CDKL3 overexpression produced the opposite effect. In conclusion, our results identified CDKL3 as a promotor for glioma, probably through the regulation of RRM2 and activation of the JNK signalling pathway, highlighting the significance of CDKL3 as a promising therapeutic target of glioma.

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References

Bradley D, Rees J . Updates in the management of high-grade glioma. J Neurol. 2013; 261(4):651-4. DOI: 10.1007/s00415-013-7032-x. View

Rudin C, Durinck S, Stawiski E, Poirier J, Modrusan Z, Shames D . Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012; 44(10):1111-6. PMC: 3557461. DOI: 10.1038/ng.2405. View

Caromile L, Dortche K, Rahman M, Grant C, Stoddard C, Ferrer F . PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer. Sci Signal. 2017; 10(470). PMC: 5545931. DOI: 10.1126/scisignal.aag3326. View

Omuro A, Faivre S, Raymond E . Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther. 2007; 6(7):1909-19. DOI: 10.1158/1535-7163.MCT-07-0047. View

Liu Z, Tao D . Inactivition of CDKL3 mildly inhibits proliferation of cells at VZ/SVZ in brain. Neurol Sci. 2014; 36(2):297-302. DOI: 10.1007/s10072-014-1952-9. View

Parsons D, Jones S, Zhang X, Cheng-Ho Lin J, Leary R, Angenendt P . An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321(5897):1807-12. PMC: 2820389. DOI: 10.1126/science.1164382. View

Midmer M, Haq R, Squire J, Zanke B . Identification of NKIAMRE, the human homologue to the mitogen-activated protein kinase-/cyclin-dependent kinase-related protein kinase NKIATRE, and its loss in leukemic blasts with chromosome arm 5q deletion. Cancer Res. 1999; 59(16):4069-74. View

Fang J, Richardson B . The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005; 6(5):322-7. DOI: 10.1016/S1470-2045(05)70168-6. View

Furnari F, Fenton T, Bachoo R, Mukasa A, Stommel J, Stegh A . Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007; 21(21):2683-710. DOI: 10.1101/gad.1596707. View

10.

Dubos A, Pannetier S, Hanauer A . Inactivation of the CDKL3 gene at 5q31.1 by a balanced t(X;5) translocation associated with nonspecific mild mental retardation. Am J Med Genet A. 2008; 146A(10):1267-79. DOI: 10.1002/ajmg.a.32274. View

11.

Maher E, Furnari F, Bachoo R, Rowitch D, Louis D, Cavenee W . Malignant glioma: genetics and biology of a grave matter. Genes Dev. 2001; 15(11):1311-33. DOI: 10.1101/gad.891601. View

12.

Burotto M, Chiou V, Lee J, Kohn E . The MAPK pathway across different malignancies: a new perspective. Cancer. 2014; 120(22):3446-56. PMC: 4221543. DOI: 10.1002/cncr.28864. View

13.

Grauer O, Wesseling P, Adema G . Immunotherapy of diffuse gliomas: biological background, current status and future developments. Brain Pathol. 2009; 19(4):674-93. PMC: 8094991. DOI: 10.1111/j.1750-3639.2009.00315.x. View

14.

Bao S, Wu Q, McLendon R, Hao Y, Shi Q, Hjelmeland A . Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444(7120):756-60. DOI: 10.1038/nature05236. View

15.

Nayak L, Reardon D . High-grade Gliomas. Continuum (Minneap Minn). 2017; 23(6, Neuro-oncology):1548-1563. DOI: 10.1212/CON.0000000000000554. View

16.

Minniti G, Muni R, Lanzetta G, Marchetti P, Enrici R . Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. Anticancer Res. 2010; 29(12):5171-84. View

17.

Jaluria P, Betenbaugh M, Konstantopoulos K, Shiloach J . Enhancement of cell proliferation in various mammalian cell lines by gene insertion of a cyclin-dependent kinase homolog. BMC Biotechnol. 2007; 7:71. PMC: 2164945. DOI: 10.1186/1472-6750-7-71. View

18.

Molinari F, Rio M, Meskenaite V, Encha-Razavi F, Auge J, Bacq D . Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science. 2002; 298(5599):1779-81. DOI: 10.1126/science.1076521. View

19.

Cui Y, Yang Z, Wang H, Yan Y, Huang Q, Gong Z . Identification of CDKL3 as a critical regulator in development of glioma through regulating RRM2 and the JNK signaling pathway. Cancer Sci. 2021; 112(8):3150-3162. PMC: 8353949. DOI: 10.1111/cas.15010. View

20.

Wang H, Song X, Huang Q, Xu T, Yun D, Wang Y . LGALS3 Promotes Treatment Resistance in Glioblastoma and Is Associated with Tumor Risk and Prognosis. Cancer Epidemiol Biomarkers Prev. 2018; 28(4):760-769. DOI: 10.1158/1055-9965.EPI-18-0638. View