The Histone Acetylranseferase HMOF Acetylates Nrf2 and Regulates Anti-drug Responses in Human Non-small Cell Lung Cancer

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2014 Feb 28

PMID 24571482

Citations 47

Authors

Zhiwei Chen

Xiangyun Ye

Naiwang Tang

Shengping Shen

Ziming Li

Xiaomin Niu

Shun Lu

Ling Xu

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: The histone acetyltransferase MOF is a member of the MYST family. In mammals, MOF plays critical roles by acetylating histone H4 at K16 and non-histone substrates such as p53. Here we have investigated the role of MOF in human lung cancer and possible new substrates of hMOF.

Experimental Approach: Samples of human non-small cell lung cancer (NSCLC) were used to correlate MOF with clinicopathological parameters and NF-E2-related factor 2 (Nrf2) downstream genes. 293T-cells were used to study interactions between MOF and Nrf2, and acetylation of Nrf2 by MOF. Mouse embryonic fibroblast and A549 cells were utilized to assess involvement of MOF in antioxidative and anti-drug responses. A549 cells were used to analysis the role of MOF in anti-drug response in vitro and in vivo.

Key Results: hMOF was overexpressed in human NSCLC tissues and was associated with large tumour size, advanced disease stage and metastasis, and with poor prognosis. hMOF levels were positively correlated with Nrf2-downstream genes. MOF/hMOF physically interacted with and acetylated Nrf2 at Lys(588) . MOF-mediated acetylation increased nuclear retention of Nrf2 and transcription of its downstream genes. Importantly, MOF/hMOF was essential for anti-oxidative and anti-drug responses in vitro and regulated tumour growth and drug resistance in vivo in an Nrf2-dependent manner.

Conclusion And Implications: hMOF was overexpressed in human NSCLC and was a predictor of poor survival. hMOF-mediated Nrf2 acetylation and nuclear retention are essential for anti-oxidative and anti-drug responses. hMOF may provide a therapeutic target for the treatment of NSCLC.

Citing Articles

Acetyltransferase in cardiovascular disease and aging.

Keller M, Nakamura M J Cardiovasc Aging. 2025; 4(26).

PMID: 39958699 PMC: 11827898. DOI: 10.20517/jca.2024.21.

The role of acetylation and deacetylation in cancer metabolism.

Wang C, Ma X Clin Transl Med. 2025; 15(1):e70145.

PMID: 39778006 PMC: 11706801. DOI: 10.1002/ctm2.70145.

HDAC8 Enhances the Function of HIF-2α by Deacetylating ETS1 to Decrease the Sensitivity of TKIs in ccRCC.

Qian K, Li W, Ren S, Peng W, Qing B, Liu X Adv Sci (Weinh). 2024; 11(36):e2401142.

PMID: 39073752 PMC: 11423204. DOI: 10.1002/advs.202401142.

Angelicin improves osteoporosis in ovariectomized rats by reducing ROS production in osteoclasts through regulation of the KAT6A/Nrf2 signalling pathway.

Liu X, Liao Y, Shao J, He D, Fan Z, Xu Y Chin Med. 2024; 19(1):91.

PMID: 38956695 PMC: 11218408. DOI: 10.1186/s13020-024-00961-7.

KAT8 enhances the resistance of lung cancer cells to cisplatin by acetylation of PKM2.

Li Z, Lu X, Zhang J, Liu T, Xu M, Liu S Anticancer Drugs. 2024; 35(8):732-740.

PMID: 38771737 PMC: 11305626. DOI: 10.1097/CAD.0000000000001622.

References

Pfister S, Rea S, Taipale M, Mendrzyk F, Straub B, Ittrich C . The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma. Int J Cancer. 2007; 122(6):1207-13. DOI: 10.1002/ijc.23283. View

Gupta A, Sharma G, Young C, Agarwal M, Smith E, Paull T . Involvement of human MOF in ATM function. Mol Cell Biol. 2005; 25(12):5292-305. PMC: 1140595. DOI: 10.1128/MCB.25.12.5292-5305.2005. View

Zhang D . Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006; 38(4):769-89. DOI: 10.1080/03602530600971974. View

Mellert H, McMahon S . hMOF, a KAT(8) with many lives. Mol Cell. 2009; 36(2):174-5. DOI: 10.1016/j.molcel.2009.10.005. View

Thomas T, Dixon M, Kueh A, Voss A . Mof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture. Mol Cell Biol. 2008; 28(16):5093-105. PMC: 2519697. DOI: 10.1128/MCB.02202-07. View

Zhao L, Wang D, Liu Y, Chen S, Sun F . Histone acetyltransferase hMOF promotes S phase entry and tumorigenesis in lung cancer. Cell Signal. 2013; 25(8):1689-98. DOI: 10.1016/j.cellsig.2013.04.006. View

Li X, Corsa C, Pan P, Wu L, Ferguson D, Yu X . MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Mol Cell Biol. 2010; 30(22):5335-47. PMC: 2976376. DOI: 10.1128/MCB.00350-10. View

Zhou Y, Schmitz K, Mayer C, Yuan X, Akhtar A, Grummt I . Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing. Nat Cell Biol. 2009; 11(8):1010-6. DOI: 10.1038/ncb1914. View

Yamadori T, Ishii Y, Homma S, Morishima Y, Kurishima K, Itoh K . Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers. Oncogene. 2012; 31(45):4768-77. DOI: 10.1038/onc.2011.628. View

10.

Jaiswal A . Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med. 2004; 36(10):1199-207. DOI: 10.1016/j.freeradbiomed.2004.02.074. View

11.

Sharma G, So S, Gupta A, Kumar R, Cayrou C, Avvakumov N . MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Mol Cell Biol. 2010; 30(14):3582-95. PMC: 2897562. DOI: 10.1128/MCB.01476-09. View

12.

Kapoor-Vazirani P, Kagey J, Powell D, Vertino P . Role of hMOF-dependent histone H4 lysine 16 acetylation in the maintenance of TMS1/ASC gene activity. Cancer Res. 2008; 68(16):6810-21. PMC: 2585755. DOI: 10.1158/0008-5472.CAN-08-0141. View

13.

Dinkova-Kostova A, Talalay P . NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys. 2010; 501(1):116-23. PMC: 2930038. DOI: 10.1016/j.abb.2010.03.019. View

14.

Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M . Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 2008; 68(5):1303-9. DOI: 10.1158/0008-5472.CAN-07-5003. View

15.

Vollrath V, Wielandt A, Iruretagoyena M, Chianale J . Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochem J. 2006; 395(3):599-609. PMC: 1462684. DOI: 10.1042/BJ20051518. View

16.

Shi X, Hong T, Walter K, Ewalt M, Michishita E, Hung T . ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature. 2006; 442(7098):96-9. PMC: 3089773. DOI: 10.1038/nature04835. View

17.

Singh A, Misra V, Thimmulappa R, Lee H, Ames S, Hoque M . Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006; 3(10):e420. PMC: 1584412. DOI: 10.1371/journal.pmed.0030420. View

18.

Li N, He Y, Wang L, Mo C, Zhang J, Zhang W . D-galactose induces necroptotic cell death in neuroblastoma cell lines. J Cell Biochem. 2011; 112(12):3834-44. DOI: 10.1002/jcb.23314. View

19.

Hilfiker A, Hilfiker-Kleiner D, Pannuti A, Lucchesi J . mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J. 1997; 16(8):2054-60. PMC: 1169808. DOI: 10.1093/emboj/16.8.2054. View

20.

Hayashi A, Suzuki H, Itoh K, Yamamoto M, Sugiyama Y . Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem Biophys Res Commun. 2003; 310(3):824-9. DOI: 10.1016/j.bbrc.2003.09.086. View