Does Subtelomeric Position of COMMD5 Influence Cancer Progression?

The COMMD proteins are a family of ten pleiotropic factors which are widely conserved throughout evolution and are involved in the regulation of many cellular and physiological processes. COMMD proteins are mainly expressed in adult tissue and their downregulation has been correlated with tumor progression and poor prognosis in cancer. Among this family, COMMD5 emerged as a versatile modulator of tumor progression. Its expression can range from being downregulated to highly up regulated in a variety of cancer types. Accordingly, two opposing functions could be proposed for COMMD5 in cancer. Our studies supported a role for COMMD5 in the establishment and maintenance of the epithelial cell phenotype, suggesting a tumor suppressor function. However, genetic alterations leading to amplification of COMMD5 proteins have also been observed in various types of cancer, suggesting an oncogenic function. Interestingly, COMMD5 is the only member of this family that is located at the extreme end of chromosome 8, near its telomere. Here, we review some data concerning expression and role of COMMD5 and propose a novel rationale for the potential link between the subtelomeric position of COMMD5 on chromosome 8 and its contrasting functions in cancer.

COMMD5/HCaRG Hooks Endosomes on Cytoskeleton and Coordinates EGFR Trafficking.

COMMD5/HCaRG is involved in tissue repair, and its low expression is associated with tumorigenicity. Cell growth, migration, and differentiation are controlled by COMMD5. We previously reported that COMMD5 inhibited the growth of renal carcinoma cells by regulating expression or phosphorylation of ErbB members. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. This study establishes the molecular mechanism by which COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and reveals its important role for EGFR transport and activity.

HCaRG/COMMD5 inhibits ErbB receptor-driven renal cell carcinoma.

Hypertension-related, calcium-regulated gene (HCaRG/COMMD5) is highly expressed in renal proximal tubules, where it contributes to the control of cell proliferation and differentiation. HCaRG accelerates tubular repair by facilitating re-differentiation of injured proximal tubular epithelial cells, thus improving mouse survival after acute kidney injury. Sustained hyper-proliferation and de-differentiation are important hallmarks of tumor progression. Here, we demonstrate that cancer cells overexpressing HCaRG maintain a more differentiated phenotype, while several of them undergo autophagic cell death. Its overexpression in mouse renal cell carcinomas led to smaller tumor size with less tumor vascularization in a homograft tumor model. Mechanistically, HCaRG promotes de-phosphorylation of the proto-oncogene erythroblastosis oncogene B (ErbB)2/HER2 and epigenetic gene silencing of epidermal growth factor receptor and ErbB3 via promoter methylation. Extracellular signal-regulated kinase, AKT and mammalian target of rapamycin which mediate ErbB-dowstream signaling pathways are inactivated by HCaRG expression. In addition, HCaRG is underexpressed in human renal cell carcinomas and more expressed in normal tissue adjacent to renal cell carcinomas of patients with favorable prognosis. Taken together, our data suggest a role for HCaRG in the inhibition of tumor progression as a natural inhibitor of the ErbB signals in cancer and as a potential prognostic marker for renal cell carcinomas.