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ABSTRACT Aberrations in epigenetic modulation dysregulate transcription, playing a critical role in the developmental process of tumors, including lung cancer. Aberrant levels of the histone

3 lysine-27 demethylase KDM6A have been found in cancer and are either positively or negatively associated with tumorigenesis and prognosis. However, the clinical relevance and functional

role of KDM6A in lung cancer is largely unknown. We found that KDM6A protein expression was higher in NSCLC tissues than in the corresponding paracancer tissues and that high KDM6A

expression was associated with poor patient prognosis. Furthermore, KDM6A knockdown in NSCLC cell lines markedly inhibited the tumorigenic phenotype both in vitro and in vivo.

Mechanistically, KDM6A colocalized and cooperated with KMT2B to reprogram the transcriptional network via regulating the cancer pathway, in which abnormal activation of the Wnt pathway is

the dominant factor. Interestingly, in NSCLC cell lines, H3K4me3 but not H3K27me2/3 or H3K4me1/2 was markedly altered upon KDM6A or KMT2B knockdown, indicating that KDM6A may act

independently of H3K27 demethylases in NSCLC. Taken together, these results indicated that KDM6A or KMT2B may be a prognostic biomarker and promising therapeutic target in NSCLC. Access

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SIMILAR CONTENT BEING VIEWED BY OTHERS HISTONE DEMETHYLASE KDM4C CONTROLS TUMORIGENESIS OF GLIOBLASTOMA BY EPIGENETICALLY REGULATING P53 AND C-MYC Article Open access 18 January 2021

SUPPRESSION OF M6A MRNA MODIFICATION BY DNA HYPERMETHYLATED _ALKBH5_ AGGRAVATES THE ONCOLOGICAL BEHAVIOR OF KRAS MUTATION/LKB1 LOSS LUNG CANCER Article Open access 20 May 2021 KDM4C

SILENCING INHIBITS CELL MIGRATION AND ENHANCES RADIOSENSITIVITY BY INDUCING CXCL2 TRANSCRIPTION IN HEPATOCELLULAR CARCINOMA Article Open access 28 April 2023 REFERENCES * Siegel RL, Miller

KD, Jemal A. Cancer statistics. 2019. 2019;69:7–34. Google Scholar  * Gridelli C, Rossi A, Carbone DP, Guarize J, Karachaliou N, Mok T, et al. Non-small-cell lung cancer. Nat Rev Dis Prim.

2015;1:15009. Article  Google Scholar  * Zhang C, Leighl NB, Wu YL, Zhong WZ. Emerging therapies for non-small cell lung cancer. J Hematol Oncol. 2019;12:45. Article  Google Scholar  * Hardy

TM, Tollefsbol TO. Epigenetic diet: impact on the epigenome and cancer. Epigenomics. 2011;3:503–18. Article  CAS  Google Scholar  * Toh TB, Lim JJ, Chow EK. Epigenetics in cancer stem

cells. Mol Cancer. 2017;16:29. Article  Google Scholar  * Ahuja N, Sharma AR, Baylin SB. Epigenetic therapeutics: a new weapon in the war against cancer. Annu Rev Med. 2016;67:73–89. Article

  CAS  Google Scholar  * Chen Y, Liu X, Li Y, Quan C, Zheng L, Huang K. Lung cancer therapy targeting histone methylation: opportunities and challenges. Comput Struct Biotechnol J.

2018;16:211–23. Article  CAS  Google Scholar  * Ju HC, Oezkan F, Koenig M, Otterson GA, Herman JG, He K. Epigenetic therapeutics and their impact in immunotherapy of lung cancer. Curr Pharm

Rep. 2017;3:360. Article  Google Scholar  * Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23:781–3. Article  CAS  Google

Scholar  * Abed Alfatah M, Ohad G, Leehee W, Asaf Z, Muneef A, Yoach R, et al. The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature. 2012;488:409–13.

Article  Google Scholar  * Fei L, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Shuzhen C, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature.

2007;449:689–94. Article  Google Scholar  * Van der Meulen J, Speleman F, Van Vlierberghe P. The H3K27me3 demethylase UTX in normal development and disease. Epigenetics. 2014;9:658–68.

Article  Google Scholar  * Xu B, Konze KD, Jin J, Wang GG. Targeting EZH2 and PRC2 dependence as novel anticancer therapy. Exp Hematol. 2015;43:698–712. Article  CAS  Google Scholar  *

Montgomery ND, Yee D, Chen A, Kalantry S, Chamberlain SJ, Otte AP, et al. The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol.

2005;15:942–7. Article  CAS  Google Scholar  * Sunhwa H, Young-Wook C, Li-Rong Y, Hong Y, Veenstra TD, Ge K. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27

demethylases. Proc Natl Acad Sci USA. 2007;104:18439–44. Article  Google Scholar  * Rao RC, Dou Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat Rev Cancer.

2015;15:334–46. Article  CAS  Google Scholar  * Ezponda T, Dupere-Richer D, Will CM, Small EC, Varghese N, Patel T, et al. UTX/ loss enhances the malignant phenotype of multiple myeloma and

sensitizes cells to EZH2 inhibition. Cell Rep. 2017;21:628–40. Article  CAS  Google Scholar  * Jankowska AM, Makishima H, Tiu RV, Szpurka H, Huang Y, Traina F, et al. Mutational spectrum

analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood. 2011;118:3932–41. Article  CAS  Google Scholar  * Joni VDM,

Viraj S, Konstantinos M, Kaat D, Fang F, Filip M, et al. The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood. 2015;125:13–21.

Article  Google Scholar  * Li SH, Lu HI, Huang WT, Tien WY, Lan YC, Lin WC, et al. The prognostic significance of histone demethylase UTX in esophageal squamous cell carcinoma. Int J Mol

Sci. 2018;19:297. Article  Google Scholar  * Li X, Zhang Y, Zheng L, Liu M, Chen CD, Jiang H. UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma. Nat Commun.

2018;9:2720. Article  Google Scholar  * Liao L, Testa JR, Yang H. The roles of chromatin-remodelers and epigenetic modifiers in kidney cancer. Cancer Genet. 2015;208:206–14. Article  CAS 

Google Scholar  * Kim JH, Sharma A, Dhar SS, Lee SH, Gu B, Chan CH, et al. UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast

cancer cells. Cancer Res. 2014;74:1705–17. Article  CAS  Google Scholar  * Tang X, Cai W, Cheng J, Lu P, Ma S, Chen C, et al. The histone H3 lysine-27 demethylase UTX plays a critical role

in colorectal cancer cell proliferation. Cancer Cell Int. 2019;19:144. Article  Google Scholar  * Wang L, Shilatifard A. UTX mutations in human cancer. Cancer Cell. 2019;35:168–76. Article 

CAS  Google Scholar  * van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C, et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet.

2009;41:521–3. Article  Google Scholar  * Ruthenburg AJ, Allis CD, Wysocka J. Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell.

2007;25:15–30. Article  CAS  Google Scholar  * Sierra J, Yoshida T, Joazeiro CA, Jones KA. The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target

genes. Genes Dev. 2006;20:586–600. Article  CAS  Google Scholar  * Fan L, Peng G, Sahgal N, Fazli L, Gleave M, Zhang Y, et al. Regulation of c-Myc expression by the histone demethylase

JMJD1A is essential for prostate cancer cell growth and survival. Oncogene. 2015;35:2441–52. Article  Google Scholar  * Audia JE, Campbell RM. Histone modifications and cancer. Cold Spring

Harb Perspect Biol. 2016;8:a019521. Article  Google Scholar  * Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, et al. Knockdown of ALR (MLL2) reveals ALR target genes and

leads to alterations in cell adhesion and growth. Mol Cell Biol. 2007;27:1889–903. Article  CAS  Google Scholar  * Herz HM, Mohan M, Garruss AS, Liang K, Takahashi YH, Mickey K, et al.

Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 2012;26:2604–20. Article  CAS  Google Scholar  * Chaochen W, Ji-Eun

L, Young-Wook C, Ying X, Qihuang J, Chengyu L, et al. UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. PNAS. 2012;109:15324–9.

Article  Google Scholar  * Shpargel KB, Sengoku T, Yokoyama S, Magnuson T. UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS Genet.

2012;8:e1002964. Article  CAS  Google Scholar  * Kalkat M, De Melo J, Hickman KA, Lourenco C, Redel C, Resetca D, et al. MYC deregulation in primary human cancers. Genes. 2017;8:151. Article

  Google Scholar  * Mariann BJCB. beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr Biol. 2005;15:R64–R67. * Ng LF, Kaur P, Bunnag N, Suresh J, Sung ICH, Tan QH, et al.

WNT signaling in disease. Cells. 2019;8:7714. Article  Google Scholar  * Akiri G, Cherian MM, Vijayakumar S, Liu G, Bafico A, Aaronson SA. Wnt pathway aberrations including autocrine Wnt

activation occur at high frequency in human non-small-cell lung carcinoma. Oncogene. 2009;28:2163–72. Article  CAS  Google Scholar  * Sun L, Song L, Wan Q, Wu G, Li X, Wang Y, et al.

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Res. 2015;25:429–44. Article  CAS  Google Scholar  *

Dang CV. MYC on the path to cancer. Cell. 2012;149:22–35. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Drs Meiyu Geng and Jing Ai (Shanghai Institute of

Materia Medica, Chinese Academy of Sciences) and other members of Dr. Meiyu Geng’s laboratory for their assistance in lab work. FOUNDING This research was supported by National Natural

Science Foundation of China (Grant no. 81572250). AUTHOR INFORMATION Author notes * These authors contributed equally: Xuejiao Leng, Jianfeng Wang, Na An AUTHORS AND AFFILIATIONS * Shanghai

Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China Xuejiao Leng, Na An, Xue Wang, Yile Sun & Zhiwei Chen * Department of Urology,

Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China Jianfeng Wang Authors * Xuejiao Leng View author publications You can also search for this author inPubMed 

Google Scholar * Jianfeng Wang View author publications You can also search for this author inPubMed Google Scholar * Na An View author publications You can also search for this author

inPubMed Google Scholar * Xue Wang View author publications You can also search for this author inPubMed Google Scholar * Yile Sun View author publications You can also search for this

author inPubMed Google Scholar * Zhiwei Chen View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS XJL performed experiments and wrote the main

manuscript. NA collected tumor samples and the clinical data. JFW was responsible for all statistical analysis. XW and YLS checked relevant documents. ZWC designed this study and directed

the overall project. All authors reviewed the manuscript. CORRESPONDING AUTHOR Correspondence to Zhiwei Chen. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no

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SUPPLEMENTARY INFORMATION SUPPLEMENTARY DATA RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Leng, X., Wang, J., An, N. _et al._ Histone 3 lysine-27

demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3. _Oncogene_ 39, 6468–6479 (2020). https://doi.org/10.1038/s41388-020-01449-y Download

citation * Received: 14 January 2020 * Revised: 16 August 2020 * Accepted: 24 August 2020 * Published: 02 September 2020 * Issue Date: 08 October 2020 * DOI:

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