HIST1H3D: A promising therapeutic target for lung cancer

Int J Oncol. 2017 Mar;50(3):815-822. doi: 10.3892/ijo.2017.3856. Epub 2017 Jan 19.


HIST1H3D gene encodes histone H3.1 and is involved in gene-silencing and heterochromatin formation. HIST1H3D expression is upregulated in primary gastric cancer tissue. In this study, we explored the effects of HIST1H3D expression on lung cancer, and its mechanisms. HIST1H3D expression was measured by immunohistochemistry and RT-PCR in lung cancer tissues and human lung cancer cell lines. Cell proliferation was assessed by MTT assay. Flow cytometric analysis was used to determine cell cycle distribution and apoptosis. Levels of related proteins were detected by western blotting. Bioinformatics analysis was performed to investigate related signaling pathways. cDNA microarray analysis was performed to identify differentially expressed genes following HIST1H3D knockdown. HIST1H3D expression was upregulated in lung cancer tissue samples and the H1299 human lung cancer cell line (P<0.01). Regulation of HIST1H3D expression in nucleus of cells in lung cancer tissues was significant associated with tumor stage (P=0.02) and lymph node metastases (P=0.04). Downregulation of HIST1H3D expression led to suppression of proliferation and colony forming ability, cell cycle arrest at the G0/G1 phase, and promotion of cell apoptosis. The microarray data revealed 522 genes that were differentially expressed after HIST1H3D knockdown in H1299 cells. These genes were shown to be linked to numerous pathways, including the cell cycle, p53 signaling, and MCM. Western blot analysis confirmed upregulated expression of the THBS1 and TP53I3 genes, and downregulated expression of the CDK6, CDKN1 and CCNE2 genes. In conclusion, our results suggest that HIST1H3D is highly expressed in lung cancer cell lines and tissues. Furthermore, HIST1H3D may be important in cell proliferation, apoptosis and cell cycle progression, and is implicated as a potential therapeutic target for lung cancer.

MeSH terms

  • A549 Cells
  • Apoptosis / genetics*
  • Cell Cycle / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclins / metabolism
  • Down-Regulation
  • Female
  • G1 Phase Cell Cycle Checkpoints
  • Gene Expression Regulation, Neoplastic
  • Histones / genetics*
  • Histones / metabolism
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Lymphatic Metastasis / genetics
  • Male
  • Middle Aged
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Signal Transduction / genetics
  • Thrombospondin 1 / metabolism
  • Tumor Suppressor Protein p53 / metabolism


  • CCNE2 protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Histones
  • RNA, Small Interfering
  • TP53 protein, human
  • Thrombospondin 1
  • Tumor Suppressor Protein p53
  • thrombospondin-1, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6