UbcH10 overexpression increases carcinogenesis and blocks ALLN susceptibility in colorectal cancer.

Abstract

Cyclins are essential for cell proliferation, the cell cycle and tumorigenesis in all eukaryotes. UbcH10 regulates the degradation of cyclins in a ubiquitin-dependent manner. Here, we report that UbcH10 is likely involved in tumorigenesis. We found that cancer cells exposed to n-acetyl-leu-leu-norleucinal (ALLN) treatment and UbcH10 depletion exhibit a synergistic therapeutic effect. Abundant expression of UbcH10 drives resistance to ALLN-induced cell death, while cells deficient in UbcH10 were susceptible to ALLN-induced cell death. The depletion of UbcH10 hindered tumorigenesis both in vitro and in vivo, as assessed by colony formation, growth curve, soft agar and xenograft assays. These phenotypes were efficiently rescued through the introduction of recombinant UbcH10. In the UbcH10-deficient cells, alterations in the expression of cyclins led to cell cycle changes and subsequently decreases in tumorigenesis. The tumorigenesis of xenograft tumors from UbcH10-deficient cells treated with ALLN was decreased relative to wild-type cells treated with ALLN in nude mice. On the molecular level, we observed that UbcH10 deficiency enhances the activation of caspase 8 and caspase 3 but not caspase 9 to impair cell viability upon ALLN treatment. Collectively, our results suggest that, as an oncogene, UbcH10 is a potential drug target for the treatment of colorectal cancer.

• Authors: Shang-Ze Li, Yang Song, Hui-Hui Zhang, Bing-Xue Jin, Yi Liu, Wen-Bin Liu, Xiao-Dong Zhang, Run-Lei Du
• Journal: Scientific reports (Sci Rep) Vol. 4 Pg. 6910 (Nov 07 2014) ISSN: 2045-2322 [Electronic] England
• PMID: 25376843 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclins
• Leupeptins
• Ubiquitin
• acetylleucyl-leucyl-norleucinal
• UBE2C protein, human
• Ubiquitin-Conjugating Enzymes
• Caspases

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
• Animals
• Carcinogenesis (drug effects, genetics, metabolism, pathology)
• Caspases (genetics, metabolism)
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cyclins (genetics, metabolism)
• Dependovirus (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Vectors
• Humans
• Leupeptins (pharmacology)
• Mice
• Mice, Knockout
• Mice, Nude
• Signal Transduction
• Ubiquitin (genetics, metabolism)
• Ubiquitin-Conjugating Enzymes (deficiency, genetics, pharmacology)
• Xenograft Model Antitumor Assays