Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22

Abstract

Deletions in the 8p21-22 region of the human genome are among the most common genetic alterations in prostate carcinomas. Several studies in di erent tumor tissues, including prostate, indicate that there are probably multiple tumor suppressor genes (TSGs) present in this region. To identify candidate TSGs on 8p22 a YAC contig spanning this region was assembled and YAC clones retro®tted with a selectable marker (neo) were transferred into rat prostate AT6.2 cells. Two overlapping YAC clones showed greatly reduced colonyforming e ciency, indicating they may carry a TSG. Two BAC clones encompassing the overlapping region also appeared to exert suppressive e ects on the growth of AT6.2 cells. Database searches for genes mapped to the critical region identi®ed a gene known as FEZ1 (LZTS1) as a potential candidate suppressor gene. Subsequent experiments showed that over-expression of LZTS1 cDNA inhibited stable colony-forming e ciencies of AT6.2, HEK-293 and LNCaP cells. In contrast, LZTS1-transfected Rat-1 and RM1 cells were growthstimulated. Database searches also identi®ed additional isoforms of the LZTS1 mRNA, as well as LZTS1 protein domains reminiscent of those found in transcription factors. Together these data suggest that the LZTS1 gene is involved in the regulation of cell growth and its loss of function may contribute to the development of prostatic carcinomas, as well as other cancers. Oncogene (2001) 20, 4169 ± 4179.

LAPSER1: a novel candidate tumor suppressor gene from 10q24.3

“…The expression of the latter, which has now been designated as the LZTS1 (leucine zipper, putative tumor suppressor 1) gene, has been found to be altered in many tumors and cell lines including esophageal, breast and prostate (Ishii et al, 1999). We have also recently demonstrated this gene's ability to in¯uence cellular growth properties (Cabeza-Arvelaiz et al, 2001), which, together with the previous results, make it an excellent candidate for a TSG.…”

“…Identification and mapping of the LAPSER1 gene LZTS1 (also known as FEZ1) has been suggested as a candidate TSG on the basis of its frequent deletion in various cancers (Ishii et al, 1999) and its recent functional identi®cation as a cell growth suppressing gene on 8p22 (Cabeza-Arvelaiz et al, 2001). When BLAST searches were performed with the LZTS1 gene sequence against the GenBank databases, we identi®ed three other related human genes of unknown function, as shown in the dendogram in Figure 1a.…”

Progressive increase of genetic alteration in urinary bladder cancer by combined allelotyping analysis and comparative genomic hybridization

“…Homozygous deletion has also been identified in prostate cancer and medulloblastoma (34)(35)(36) suggesting that multiple TSGs are located in this region. Fez1/Lzts1 (leucine zipper, putative tumor suppressor 1) is a potential tumor suppressor gene located at this region (37). Expression of FEZ1/LZTS1 was reduced or absent in lung, gastric and bladder cancer (38)(39)(40).…”

DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity

“…Similarly, DNA copy-number losses in this region were identified by comparative genomic hybridization (CGH) in tumors of the breast, liver, colon, lung, ovary, bladder and prostate, as well as in osteosarcomas, mesotheliomas, B-cell lymphomas and mantle cell lymphoma (Martinez-Climent et al, 2001;Zitzelsberger et al, 1997). Chromosome 8 transfer into colon and prostate tumor cell lines provided functional evidence for the presence of tumor suppressor genes on chromosome 8p21-22 (Gustafson et al, 1996;Cabeza-Arvelaiz et al, 2001).…”