hMOF reduction enhances radiosensitivity through the homologous recombination pathway in non-small-cell lung cancer

Purpose: Human males absent on the first (hMOF) is a histone acetyltransferase (HAT) and is responsible for acetylating histone H4 at lysine 16 (H4K16). Recent studies have indicated that hMOF is overexpressed in non-small-cell lung cancer (NSCLC) as an oncogene. The aim of this study is to profile the prognostic roles of hMOF in patients with unresectable stage III NSCLC undergoing definitive radiotherapy (RT) and in the radiosensitivity of human NSCLC cells. Materials and methods: The expression of hMOF was detected in 24 normal and tumor-paired fresh-frozen NSCLC tissue samples. The immunohistochemistry was conducted, and the correlation of hMOF with clinicopathological parameters was studied in tissues from 90 patients with unresectable stage III NSCLC who underwent definitive RT. Radiation sensi-tivity was monitored using clonogenic assays in NCI-H1299 and A549 NSCLC cell lines with hMOF knockdown. Results: hMOF was overexpressed in NSCLC tissues compared with non-cancerous tissues. Compared to patients with downregulated hMOF, upregulated hMOF was observed in 51.1% (46/90) of the patients, who showed a significantly worse 5-year survival rate (5.4% vs 22.9%, P = 0.025). hMOF expression was an independent prognostic factor of unresectable stage III NSCLC patients who underwent definitive RT. Silencing hMOF increased in vitro the sensitive enhancing ratio (SER) of NSCLC cell lines and downregulated the expression of phospho-ataxia telangiectasia mutated (p-ATM) and RAD51 after irradiation (IR). Conclusion: Overexpression of hMOF predicts poor prognosis in patients with unresectable stage III NSCLC undergoing definitive RT. Downregulating hMOF might be a promising intervention to improve the outcome after RT. biomarkers and effective radiosensitizers has important clinical significance for improving the therapeutic efficacy of NSCLC patients. groups, which indicated that hMOF may affect the protein expression of raD51 at the level of transcription (* P , 0.05). Abbreviations: ATM, ataxia telangiectasia mutated; hMOF, human males absent on the first; H4K16ac, acetylated H4K16; IR, irradiation; NSCLC, lung p-ATM, phospho-ataxia telangiectasia mutated; RT-PCR, real-time PCR.

[1]  C. Simone,et al.  Radiation Treatment Time and Overall Survival in Locally Advanced Non-small Cell Lung Cancer. , 2017, International journal of radiation oncology, biology, physics.

[2]  M. Joerger,et al.  RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies , 2017, International journal of cancer.

[3]  W. Curran,et al.  Evaluating Intensity-Modulated Radiation Therapy in Locally Advanced Non-Small-Cell Lung Cancer: Results From the National Cancer Data Base. , 2016, Clinical lung cancer.

[4]  C. Oing,et al.  Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation , 2015, Nucleic acids research.

[5]  Shun Lu,et al.  The histone acetylranseferase hMOF acetylates Nrf2 and regulates anti‐drug responses in human non‐small cell lung cancer , 2014, British journal of pharmacology.

[6]  D. Sher,et al.  Influence of conformal radiotherapy technique on survival after chemoradiotherapy for patients with stage III non‐small cell lung cancer in the National Cancer Data Base , 2014, Cancer.

[7]  Su Chen,et al.  Histone acetyltransferase hMOF promotes S phase entry and tumorigenesis in lung cancer. , 2013, Cellular signalling.

[8]  Xian-hong Liu,et al.  RNAi screening identifies KAT8 as a key molecule important for cancer cell survival. , 2013, International journal of clinical and experimental pathology.

[9]  Benjamin Movsas,et al.  Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. , 2011, Journal of the National Cancer Institute.

[10]  David J. Chen,et al.  MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair , 2010, Molecular and Cellular Biology.

[11]  Jose Belderbos,et al.  Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  I. Grummt,et al.  Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing , 2009, Nature Cell Biology.

[13]  S. Sykes,et al.  Acetylation of the DNA Binding Domain Regulates Transcription-independent Apoptosis by p53* , 2009, The Journal of Biological Chemistry.

[14]  Nicholas M. Luscombe,et al.  Genome-wide Analysis Reveals MOF as a Key Regulator of Dosage Compensation and Gene Expression in Drosophila , 2008, Cell.

[15]  Y. Matsumoto,et al.  Ability to repair DNA double-strand breaks related to cancer susceptibility and radiosensitivity , 2007, Radiation Medicine.

[16]  T. Ludwig,et al.  The Mammalian Ortholog of Drosophila MOF That Acetylates Histone H4 Lysine 16 Is Essential for Embryogenesis and Oncogenesis , 2007, Molecular and Cellular Biology.

[17]  S. Rea,et al.  Males absent on the first (MOF): from flies to humans , 2007, Oncogene.

[18]  Ronen Marmorstein,et al.  Acetylation of the p53 DNA-binding domain regulates apoptosis induction. , 2006, Molecular cell.

[19]  William Arbuthnot Sir Lane,et al.  A Human Protein Complex Homologous to the Drosophila MSL Complex Is Responsible for the Majority of Histone H4 Acetylation at Lysine 16 , 2005, Molecular and Cellular Biology.

[20]  P. Lichter,et al.  hMOF Histone Acetyltransferase Is Required for Histone H4 Lysine 16 Acetylation in Mammalian Cells , 2005, Molecular and Cellular Biology.

[21]  T. Ludwig,et al.  Involvement of Human MOF in ATM Function , 2005, Molecular and Cellular Biology.

[22]  M. Fraga,et al.  Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer , 2005, Nature Genetics.

[23]  T. Pandita.  A multifaceted role for ATM in genome maintenance , 2003, Expert Reviews in Molecular Medicine.

[24]  Y. Shiloh.  ATM and related protein kinases: safeguarding genome integrity , 2003, Nature Reviews Cancer.

[25]  P. Becker,et al.  Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. , 2000, Molecular cell.

[26]  J. Lucchesi,et al.  A new human member of the MYST family of histone acetyl transferases with high sequence similarity to Drosophila MOF. , 2000, Biochimica et biophysica acta.

[27]  A. Jemal,et al.  Cancer statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[28]  S. Jang,et al.  The Histone Acetyltransferase hMOF is Overexpressed in Non-small Cell Lung Carcinoma , 2011 .

[29]  G. Murphy.  The national cancer data base , 1991, CA: a cancer journal for clinicians.

[30]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.