Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin.
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.
Wagner
Klaus W
KW
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Sapinoso
Lisa M
LM
El-Rifai
Wa'el
W
Frierson
Henry F
HF
Butz
Nicole
N
Mestan
Juergen
J
Hofmann
Francesco
F
Deveraux
Quinn L
QL
Hampton
Garret M
GM
D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors*
D017931:DNA Primers; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes