Abstract
ING5 belongs to the Inhibitor of Growth (ING) candidate tumor suppressor family, whose functions have been involved in the regulation of chromatin remodeling, cell cycle progression, proliferation and apoptosis. Our previous study has shown that ING5 overexpression inhibits lung cancer aggressiveness via suppressing epithelial to mesenchymal transition (EMT). However, the mechanisms remain largely unknown. In the current study, by Phospho-Kinase array and western blot, we have defined significantly upregulated EGFR/PI3K/Akt and IL-6/STAT3 oncogenic signaling pathways in ING5 knockdown A549 cells, which could be downregulated by ING5 overexpression. PI3K inhibitor ZSTK474 or STAT3 inhibitor Niclosamide not only abolished ING5 knockdown-promoted proliferation, colony formation, migration and invasion of lung cancer A549 cells, but also impaired ING5 knockdown-stimulated metastasis of cancer cells in mouse xenograft models with tail vein injection of A549 cells. Furthermore, treatment with ZSTK474 or Niclosamide decreased protein level of EGFR, p-Akt, IL-6 and p-STAT3, and reversed ING5 knockdown-promoted EMT, as indicated by downregulated expression of EMT marker E-cadherin, an epithelial marker, increased expression of N-cadherin, a mesenchymal marker, and EMT-related transcription factors including Snail, Slug, Smad3 and Twist. Taken together, these results demonstrate that loss of ING5 enhances aggressiveness of lung cancer cells by promoting EMT via activation of EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways.
Highlights
The proteins of the Inhibitor of Growth (ING) candidate tumor suppressor family include ING1-ING5, which share a highly conserved carboxy-terminal plant homeodomain (PHD) and are involved in multiple cellular functions such as cell cycle regulation, senescence, apoptosis, chromatin remodeling and regulation of autophagy and differentiation [1,2,3,4]
We have demonstrated that ING5 overexpression increased E-cadherin, while decreased N-cadherin, Snail and Slug, which could be reversed by ING5 knockdown in A549 cells
These results indicate that loss of ING5 promotes lung cancer invasion by inducing epithelial to mesenchymal transition (EMT)
Summary
The proteins of the Inhibitor of Growth (ING) candidate tumor suppressor family include ING1-ING5, which share a highly conserved carboxy-terminal plant homeodomain (PHD) and are involved in multiple cellular functions such as cell cycle regulation, senescence, apoptosis, chromatin remodeling and regulation of autophagy and differentiation [1,2,3,4]. ING5 has been identified as a component of genetic interacting network to control epidermal differentiation and protect epidermal stem cells from premature differentiation [9]. These results suggest that ING5 may function as a tumor suppressor through multiple mechanisms. The underlying molecular mechanisms and signaling pathways of ING5 function are still unclear
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