Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin

Abstract

Gene expression profiling of anatomically diverse carcinomas and their corresponding normal tissues was used to identify genes with cancer-associated expression. We show here that the ubiquitin conjugase, UbcH10, is significantly overexpressed in many different types of cancers and is associated with the degree of tumor differentiation in carcinomas of the breast, lung, ovary and bladder, as well as in glioblastomas. We also show that UbcH10 overexpression in gastro-esophageal, and probably other carcinomas may be a direct consequence of chromosomal amplification at the UbcH10 locus, 20q13.1, a region known to be amplified in diverse tumors. To evaluate whether inhibition of UbcH10 function may be therapeutically relevant in cancer, we used small interfering RNAs (siRNAs) to silence UbcH10 transcription selectively. Diminution of UbcH10 expression significantly inhibited both tumor and normal cell proliferation without inducing cell death. However, when combined with agonists of the DR5/TRAIL receptor, siRNAs directed against the UbcH10 transcript dramatically enhanced killing of cancer cells, but not of proliferating primary human epithelial cells or fibroblasts. Together, these data demonstrate that UbcH10 plays an important role in tumor development and that its inhibition in combination with agonists of the TRAIL receptor may provide an enhanced therapeutic index.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Arvand A, Bastians H, Welford SM, Thompson AD, Ruderman JV and Denny CT . (1998). Oncogene, 17, 2039–2045.

  • Borkhardt A . (2002). Cancer Cell, 2, 167–168.

  • Boye J, Elter T and Engert A . (2003). Ann. Oncol., 14, 520–535.

  • Cuthill S, Agarwal P, Sarkar S, Savelieva E and Reznikoff CA . (1999). Genes Chromosomes Cancer, 26, 304–311.

  • Deveraux Q, Takahashi R, Salvesen GS and Reed JC . (1997). Nature, 388, 300–303.

  • Deveraux QL and Reed JC . (1999). Genes Dev., 13, 239–252.

  • El-Rifai W, Frierson Jr HF, Moskaluk CA, Harper JC, Petroni GR, Bissonette EA, Jones DR, Knuutila S and Powell SM . (2001). Gastroenterology, 121, 592–598.

  • Fulda S and Debatin KM . (2004). Cancer Res., 64, 337–346.

  • Goke R, Goke A, Goke B, El-Deiry WS and Chen Y . (2001). Digestion, 64, 75–80.

  • Grunwald V and Hidalgo M . (2003). J. Natl. Cancer Inst., 95, 851–867.

  • Harper JW, Burton JL and Solomon MJ . (2002). Genes Dev., 16, 2179–2206.

  • Jazaeri AA, Lu K, Schmandt R, Harris CP, Rao PH, Sotiriou C, Chandramouli GV, Gershenson DM and Liu ET . (2003). Mol. Carcinogen., 36, 53–59.

  • Jin Z, Dicker DT and El-Deiry WS . (2002). Cell Cycle, 1, 82–89.

  • LaTulippe E, Satagopan J, Smith A, Scher H, Scardino P, Reuter V and Gerald WL . (2002). Cancer Res., 62, 4499–4506.

  • LeBlanc HN and Ashkenazi A . (2003). Cell Death Differ., 10, 66–75.

  • Mayer RJ . (2000). Nat. Rev. Mol. Cell Biol., 1, 145–148.

  • O'Dwyer ME and Druker BJ . (2000). Lancet Oncol., 1, 207–211.

  • Okamoto Y, Ozaki T, Miyazaki K, Aoyama M, Miyazaki M and Nakagawara A . (2003). Cancer Res., 63, 4167–4173.

  • Peters JM . (2002). Mol. Cell, 9, 931–943.

  • Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally N, Ghosh D, Barette T, Pandey A and Chinnaiyan AM . (2004). Neoplasia, 6, 1–6.

  • Salvesen GS and Dixit VM . (1997). Cell, 91, 443–446.

  • Sebti SM and Hamilton AD . (2000). Oncogene, 19, 6584–6593.

  • Stennicke HR . (2000). Symp. Soc. Exp. Biol., 52, 13–29.

  • Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T, Orth AP, Vega RG, Sapinoso LM, Moqrich A, Patapoutian A, Hampton GM, Schultz PG and Hogenesch JB . (2002). Proc. Natl. Acad. Sci. USA, 99, 4465–4470.

  • Townsley FM, Aristarkhov A, Beck S, Hershko A and Ruderman JV . (1997). Proc. Natl. Acad. Sci. USA, 94, 2362–2367.

  • Watanabe T, Imoto I, Katahira T, Hirasawa A, Ishiwata I, Emi M, Takayama M, Sato A and Inazawa J . (2002). Jpn. J. Cancer Res., 93, 1114–1122.

  • Welsh JB, Sapinoso LM, Kern SG, Brown DA, Liu T, Bauskin AR, Ward RL, Hawkins NJ, Quinn DI, Russell PJ, Sutherland RL, Breit SN, Moskaluk CA, Frierson HFJ and Hampton GM . (2003). Proc. Natl. Acad. Sci. USA, 100, 3410–3415.

  • Welsh JB, Sapinoso LM, Su AI, Kern SG, Wang-Rodriguez J, Moskaluk CA, Frierson HFJ and Hampton GM . (2001a). Cancer Res., 61, 5974–5978.

  • Welsh JB, Zarrinkar PP, Sapinoso LM, Kern SG, Behling CA, Monk BJ, Lockhart DJ, Burger RA and Hampton GM . (2001b). Proc. Natl. Acad. Sci. USA, 98, 1176–1181.

  • Yamanaka A, Hatakeyama S, Kominami K, Kitagawa M, Matsumoto M and Nakayama K . (2000). Mol. Biol. Cell, 11, 2821–2831.

Download references

Acknowledgements

We thank Dr Pedro Aza-Blanc for design of one of the UbcH10 siRNAs, siUbcH10-495 (siUbcH10), Dr Marc Nasoff and Ms Deborah Knee for the agonistic DR5-A antibody and Drs Kim Quon, Marc Nasoff and Claudio Joazeiro for critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Garret M Hampton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wagner, K., Sapinoso, L., El-Rifai, W. et al. Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin. Oncogene 23, 6621–6629 (2004). https://doi.org/10.1038/sj.onc.1207861

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207861

Keywords

This article is cited by

Search

Quick links