CHCHD2 Is Coamplified with EGFR in NSCLC and Regulates Mitochondrial Function and Cell Migration

Abstract

Coiled-coil-helix-coiled-coil-helix domain-containing 2, a mitochondrial protein, encoded by CHCHD2 is located at chromosome 7p11.2 and proximal to the EGFR gene. Here, bioinformatic analyses revealed that CHCHD2 is consistently coamplified with EGFR in non-small cell lung carcinoma (NSCLC). In addition, CHCHD2 and EGFR protein expression levels were positively correlated and upregulated relative to normal lung in NSCLC tumor-derived xenografts. Knockdown of CHCHD2 expression in NSCLC cells attenuated cell proliferation, migration, and mitochondrial respiration. CHCHD2 protein-protein interactions were assessed by the complementary approaches of affinity purification mass spectrometry and in vivo proximity ligation. The CHCHD2 interactome includes the apparent hub proteins C1QBP (a mitochondrial protein) and YBX1 (an oncogenic transcription factor), and an overlapping set of hub-associated proteins implicated in cell regulation.Implications: CHCHD2 influences mitochondrial and nuclear functions and contributes to the cancer phenotype associated with 7p11.2 amplification in NSCLC. Mol Cancer Res; 13(7); 1119-29. Ó2015 AACR.

Integrated Omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact

“…2a), and elevated on average eightfold in primary and sevenfold in PDX tumours (Table 1). CHCHD2 promotes cell migration and regulates oxidative phosphorylation both at the protein level in mitochondria and transcriptionally [30][31][32][33] . Therefore, elevated expression of CHCHD2 may contribute to increased mitochondrial function and cell motility in NSCLC 34 .…”

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

“…CHCHD10 and its 243 paralogue CHCHD2, which are encoded by genes localized on chromosomes 22q11.23 and 244 7p11.2, respectively, have emerged as a result of gene duplication during the evolution from 245 yeast to man [49]. Human CHCHD2 is essential for optimal respiratory activity [100][101][102], in 246 particular that of CIV [100,102]. CHCHD2 depletion reduces the expression of the mtDNA-247 encoded COX2 subunit of CIV [100].…”

“…Overexpression of CHCHD2 results from increased gene transcription [106,107] or from the 273 coamplification of CHCHD2 with EGFR in non-small cell lung cancer (NSCLC) [101] 274 (Table 2). CHCHD2 is a survival protein, and its depletion sensitizes cancer cells to 275 genotoxic chemotherapeutics and tyrosine kinase inhibitors [107].…”

“…CHCHD2 is a survival protein, and its depletion sensitizes cancer cells to 275 genotoxic chemotherapeutics and tyrosine kinase inhibitors [107]. In addition, CHCHD2 may 276 increase cellular migration [101,108]. However, it remains to be understood through which 277 precise mechanisms CHCHD2 may contribute to malignancy.…”

Orphan proteins of unknown function in the mitochondrial intermembrane space proteome: New pathways and metabolic cross-talk

“…Interestingly, Liu et al discuss hCHCHD2 as one of the negative regulators of mitochondria-mediated apoptosis with no known homology to the Bcl-2 family, while Singleton detected mutations in the hCHCHD2 gene of late onset Parkinson patients [65], [66]. Furthermore, Wei and co-authors expand the role of this protein towards cell migration regulation and cancer [67]. This protein is therefore one of the candidates which supports the underestimated role of the IMS proteome as being involved in a complex communication system within the cell.…”