CHCHD2 mediates glioblastoma cell proliferation, mitochondrial metabolism, hypoxia­induced invasion and therapeutic resistance.

Glioblastoma (GBM) is the most common and malignant primary brain tumor affecting adults and remains incurable. The mitochondrial coiled­coil­helix­coiled­coil­helix domain­containing protein 2 (CHCHD2) has been demonstrated to mediate mitochondrial respiration, nuclear gene expression and cell migration; however, evidence of this in GBM is lacking. In the present study, it was hypothesized that CHCHD2 may play a functional role in U87 GBM cells expressing the constitutively active epidermal growth factor receptor variant III (EGFRvIII). The amplification of the CHCHD2 gene was found to be associated with a decreased patient overall and progression­free survival. The CHCHD2 mRNA levels were increased in high­vs. low­grade glioma, IDH­wt GBMs, and in tumor vs. non­tumor tissue. Additionally, CHCHD2 protein expression was greatest in invasive, EGFRvIII­expressing patient­derived samples. The CRISPR­Cas9­mediated knockout of CHCHD2 in EGFRvIII­expressing U87 cells resulted in an altered mitochondrial respiration and glutathione status, in decreased cell growth and invasion under both normoxic and hypoxic conditions, and in an enhanced sensitivity to cytotoxic agents. CHCHD2 was distributed in both the mitochondria and nuclei of U87 and U87vIII cells, and the U87vIII cells exhibited a greater nuclear expression of CHCHD2 compared to isogenic U87 cells. Incubation under hypoxic conditions, serum starvation and the reductive unfolding of CHCHD2 induced the nuclear accumulation of CHCHD2 in both cell lines. Collectively, the findings of the present study indicate that CHCHD2 mediates a variety of GBM characteristics, and highlights mitonuclear retrograde signaling as a pathway of interest in GBM cell biology.

Knockdown of CHCHD2 inhibits migration and angiogenesis of human renal cell carcinoma: A potential molecular marker for treatment of RCC.

Coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2), a novel cell migration determinant, is able to co-express with other genes of the oxidative phosphorylation pathway by using a computational expression screening technique. However, little is known about the expression and biological function of CHCHD2 in human renal cell carcinoma (RCC). Western blotting was performed to detect CHCHD2 expression levels in normal renal cells and carcinoma cells. Immunohistochemistry was performed to detect an association between CHCHD2 expression and clinicopathological parameters in 75 RCC tissues using a tissue microarray. The function of CHCHD2 in the migration and angiogenesis of RCC cells was investigated using Transwell migration and tube formation assays. CHCHD2 expression was markedly increased in human RCC cells. The results of immunohistochemical analysis revealed that CHCHD2 expression was markedly associated with tumor grade (P<0.001). Notably, CHCHD2 knockdown inhibited RCC migration and tube formation of human umbilical vascular endothelial cells. CHCHD2 knockdown further suppressed matrix metalloproteinase-2 protein levels and enzyme activity. An ELISA identified that CHCHD2 knockdown decreased the secretion of vascular endothelial growth factor. The gathered data disclose information on the association of CHCHD2 with migration and angiogenesis of human RCC, and may strengthen the feasibility of targeting CHCHD2 as a potential therapeutic target.