A screen for genes that suppress loss of contact inhibition: Identification of ING4 as a candidate tumor suppressor gene in human cancer

doi:10.1073/pnas.0407158101

A screen for genes that suppress loss of contact inhibition: Identification of ING4 as a candidate tumor suppressor gene in human cancer

^*The G. W. Hooper Research Foundation and Department of Microbiology and Immunology, ^‡Department of Laboratory Medicine and Comprehensive Cancer Center, University of California, San Francisco, CA 94143; and ^§Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720

Contributed by J. Michael Bishop, September 28, 2004

Abstract

We have devised a screen for genes that suppress the loss of contact inhibition elicited by overexpression of the protooncogene MYCN. The initial application of this screen detected nine distinctive suppressors within a representative human cDNA library. One of these genes was ING4, a potential tumor suppressor gene that maps to human chromosome 12p13. Ectopic expression of ING4 suppressed the loss of contact inhibition elicited by either MYCN or MYC but had no direct effect on cellular proliferation. Pursuing the possibility that ING4 might be a tumor suppressor gene, we found inactivating mutations in ING4 transcripts from various human cancer cell lines. In addition, we used comparative genomic hybridization to detect deletion of the ING4 locus in 10-20% of human breast cancer cell lines and primary breast tumors. Ectopic expression of ING4 attenuated the growth of T47D human breast cancer cells in soft agar. We conclude that ING4 is a strong candidate as a tumor suppressor gene.

Footnotes

↵ † To whom correspondence should be addressed at: University of California, Box 0552 HSW1536, 513 Parnassus Avenue, San Francisco, CA 94143. E-mail: suwon{at}itsa.ucsf.edu.
Author contributions: S.K. designed and performed research and wrote the paper; S.K., K.C., and J.W.G. contributed new reagents/analytic tools; S.K. and K.C. analyzed data; and J.M.B. supervised research.
Abbreviations: AZT, azido-thymidine; 5-FU, 5-fluorouracil; 4-OHT, 4-hydroxy-tamoxifen; CGH, comparative genomic hybridization; IRES, internal ribosome entry site; tTA, tetracycline-responsive transcription factor.