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The tumor suppressor gene KCTD11REN is regulated by Sp1 and methylation and its expression is reduced in tumors.

Mancarelli MM, Zazzeroni F, Ciccocioppo L, Capece D, Po A, Murgo S, Di Camillo R, Rinaldi C, Ferretti E, Gulino A, Alesse E - Mol. Cancer (2010)

Bottom Line: A novel TSG mapping on human chromosome 17p13.2 is KCTD11REN (KCTD11).We have recently demonstrated that KCTD11 expression is frequently lost in human medulloblastoma (MB), in part by LOH and in part by uncharacterized epigenetic events.Additionally, in order to characterize the regulatory regions in KCTD11 promoter, we identified a CpG island and several Sp1 binding sites on this promoter, and demonstrated that Sp1 transcription factor and DNA methylation contribute, at least in part, to regulate KCTD11 expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medicine, University of L'Aquila, L'Aquila 67100, Italy.

ABSTRACT
A hallmark of several human cancers is loss of heterozygosity (LOH) of chromosome 17p13. The same chromosomal region is also frequently hypermethylated in cancer. Although loss of 17p13 has been often associated with p53 genetic alteration or Hypermethylated in Cancer 1 (HIC1) gene hypermethylation, other tumor suppressor genes (TSGs) located in this region have critical roles in tumorigenesis. A novel TSG mapping on human chromosome 17p13.2 is KCTD11REN (KCTD11). We have recently demonstrated that KCTD11 expression is frequently lost in human medulloblastoma (MB), in part by LOH and in part by uncharacterized epigenetic events. Using a panel of human 177 tumor samples and their normal matching samples representing 18 different types of cancer, we show here that the down-regulation of KCTD11 protein level is a specific and a diffusely common event in tumorigenesis. Additionally, in order to characterize the regulatory regions in KCTD11 promoter, we identified a CpG island and several Sp1 binding sites on this promoter, and demonstrated that Sp1 transcription factor and DNA methylation contribute, at least in part, to regulate KCTD11 expression. Our findings identify KCTD11 as a widely down-regulated gene in human cancers, and provide a basis to understand how its expression might be deregulated in tumor cells.

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KCTD11 is down-regulated in several cancers. (A) Representative images of KCTD11 immunohistochemistry (IHC) of esophagus (a, b), lung (c, d), stomach (e, f), colon-rectum (g, h), urinary bladder (i, j) and thyroid (k, l) (40x magnification). Tissue arrays (Super Bio Chips; cat. n. MA, MAN, MB, MBN, MC, MCN; http://www.tissue-array.com/ver3/index.php) were incubated with 1 mg/ml affinity-purified rabbit polyclonal anti-KCTD11 antibody, as previously described [12]. (B) Graphic representation of KCTD11 IHC analysis of tissue arrays. Normal and cancer tissues were analyzed counting nuclear staining as percent point. 10 high power fields (hps 40x) were counted for each sample. Stromal and inflammatory cells were not selected for nuclear staining counting. The significance of differences between normal (N) and tumor (T) tissues means was estimated using Student's t-test. (* indicates p < 0.005; ** indicates p < 0.001). Larinx: N n = 5, T n = 7; Esophagus: N n = 9, T n = 10; Stomach: N n = 13, T n = 10; Colon-rectum: N n = 12, T n = 10; Urinary bladder: N n = 5, T n = 9; Lung: N n = 10, T n = 10; Breast: N n = 4, T n = 10; Gallbladder: N n = 8, T n = 6; Endometrium: N n = 7, T n = 10; Thyroid: N n = 10, T n = 10. n: number of cases for each group.
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Figure 1: KCTD11 is down-regulated in several cancers. (A) Representative images of KCTD11 immunohistochemistry (IHC) of esophagus (a, b), lung (c, d), stomach (e, f), colon-rectum (g, h), urinary bladder (i, j) and thyroid (k, l) (40x magnification). Tissue arrays (Super Bio Chips; cat. n. MA, MAN, MB, MBN, MC, MCN; http://www.tissue-array.com/ver3/index.php) were incubated with 1 mg/ml affinity-purified rabbit polyclonal anti-KCTD11 antibody, as previously described [12]. (B) Graphic representation of KCTD11 IHC analysis of tissue arrays. Normal and cancer tissues were analyzed counting nuclear staining as percent point. 10 high power fields (hps 40x) were counted for each sample. Stromal and inflammatory cells were not selected for nuclear staining counting. The significance of differences between normal (N) and tumor (T) tissues means was estimated using Student's t-test. (* indicates p < 0.005; ** indicates p < 0.001). Larinx: N n = 5, T n = 7; Esophagus: N n = 9, T n = 10; Stomach: N n = 13, T n = 10; Colon-rectum: N n = 12, T n = 10; Urinary bladder: N n = 5, T n = 9; Lung: N n = 10, T n = 10; Breast: N n = 4, T n = 10; Gallbladder: N n = 8, T n = 6; Endometrium: N n = 7, T n = 10; Thyroid: N n = 10, T n = 10. n: number of cases for each group.

Mentions: To analyze whether the down-regulation of KCTD11 represents a specific feature of MB, as well to other cancers, we performed a wide screening for KCTD11 expression, analyzing 177 human tumor samples and 177 normal matching samples, representing 18 different cancer types. Normal tissues, including larynx, esophagus, stomach, colon-rectum, urinary bladder, lung, breast, gallbladder and endometrium, exhibited a nuclear KCTD11 positive immunohistochemical staining between 40 to 78% (Fig. 1B), whereas the matching tumor samples showed a significant reduction of 0 to 18% of nuclear KCTD11 staining (Fig. 1A and 1B). Reduced KCTD11 expression was not observed in thyroid and kidney tumor tissues vs normal suggesting a tumorigenic specific role of KCTD11 for the above mentioned tissues (Fig. 1A and 1B and data not shown). Moreover KCTD11 was undetected both in normal and cancer tissues from liver, lymph-node and exocrine pancreas (data not shown). Together, these findings clearly indicated that selective tissues expressing KCTD11 have down-regulated this gene during tumorigenesis.


The tumor suppressor gene KCTD11REN is regulated by Sp1 and methylation and its expression is reduced in tumors.

Mancarelli MM, Zazzeroni F, Ciccocioppo L, Capece D, Po A, Murgo S, Di Camillo R, Rinaldi C, Ferretti E, Gulino A, Alesse E - Mol. Cancer (2010)

KCTD11 is down-regulated in several cancers. (A) Representative images of KCTD11 immunohistochemistry (IHC) of esophagus (a, b), lung (c, d), stomach (e, f), colon-rectum (g, h), urinary bladder (i, j) and thyroid (k, l) (40x magnification). Tissue arrays (Super Bio Chips; cat. n. MA, MAN, MB, MBN, MC, MCN; http://www.tissue-array.com/ver3/index.php) were incubated with 1 mg/ml affinity-purified rabbit polyclonal anti-KCTD11 antibody, as previously described [12]. (B) Graphic representation of KCTD11 IHC analysis of tissue arrays. Normal and cancer tissues were analyzed counting nuclear staining as percent point. 10 high power fields (hps 40x) were counted for each sample. Stromal and inflammatory cells were not selected for nuclear staining counting. The significance of differences between normal (N) and tumor (T) tissues means was estimated using Student's t-test. (* indicates p < 0.005; ** indicates p < 0.001). Larinx: N n = 5, T n = 7; Esophagus: N n = 9, T n = 10; Stomach: N n = 13, T n = 10; Colon-rectum: N n = 12, T n = 10; Urinary bladder: N n = 5, T n = 9; Lung: N n = 10, T n = 10; Breast: N n = 4, T n = 10; Gallbladder: N n = 8, T n = 6; Endometrium: N n = 7, T n = 10; Thyroid: N n = 10, T n = 10. n: number of cases for each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: KCTD11 is down-regulated in several cancers. (A) Representative images of KCTD11 immunohistochemistry (IHC) of esophagus (a, b), lung (c, d), stomach (e, f), colon-rectum (g, h), urinary bladder (i, j) and thyroid (k, l) (40x magnification). Tissue arrays (Super Bio Chips; cat. n. MA, MAN, MB, MBN, MC, MCN; http://www.tissue-array.com/ver3/index.php) were incubated with 1 mg/ml affinity-purified rabbit polyclonal anti-KCTD11 antibody, as previously described [12]. (B) Graphic representation of KCTD11 IHC analysis of tissue arrays. Normal and cancer tissues were analyzed counting nuclear staining as percent point. 10 high power fields (hps 40x) were counted for each sample. Stromal and inflammatory cells were not selected for nuclear staining counting. The significance of differences between normal (N) and tumor (T) tissues means was estimated using Student's t-test. (* indicates p < 0.005; ** indicates p < 0.001). Larinx: N n = 5, T n = 7; Esophagus: N n = 9, T n = 10; Stomach: N n = 13, T n = 10; Colon-rectum: N n = 12, T n = 10; Urinary bladder: N n = 5, T n = 9; Lung: N n = 10, T n = 10; Breast: N n = 4, T n = 10; Gallbladder: N n = 8, T n = 6; Endometrium: N n = 7, T n = 10; Thyroid: N n = 10, T n = 10. n: number of cases for each group.
Mentions: To analyze whether the down-regulation of KCTD11 represents a specific feature of MB, as well to other cancers, we performed a wide screening for KCTD11 expression, analyzing 177 human tumor samples and 177 normal matching samples, representing 18 different cancer types. Normal tissues, including larynx, esophagus, stomach, colon-rectum, urinary bladder, lung, breast, gallbladder and endometrium, exhibited a nuclear KCTD11 positive immunohistochemical staining between 40 to 78% (Fig. 1B), whereas the matching tumor samples showed a significant reduction of 0 to 18% of nuclear KCTD11 staining (Fig. 1A and 1B). Reduced KCTD11 expression was not observed in thyroid and kidney tumor tissues vs normal suggesting a tumorigenic specific role of KCTD11 for the above mentioned tissues (Fig. 1A and 1B and data not shown). Moreover KCTD11 was undetected both in normal and cancer tissues from liver, lymph-node and exocrine pancreas (data not shown). Together, these findings clearly indicated that selective tissues expressing KCTD11 have down-regulated this gene during tumorigenesis.

Bottom Line: A novel TSG mapping on human chromosome 17p13.2 is KCTD11REN (KCTD11).We have recently demonstrated that KCTD11 expression is frequently lost in human medulloblastoma (MB), in part by LOH and in part by uncharacterized epigenetic events.Additionally, in order to characterize the regulatory regions in KCTD11 promoter, we identified a CpG island and several Sp1 binding sites on this promoter, and demonstrated that Sp1 transcription factor and DNA methylation contribute, at least in part, to regulate KCTD11 expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medicine, University of L'Aquila, L'Aquila 67100, Italy.

ABSTRACT
A hallmark of several human cancers is loss of heterozygosity (LOH) of chromosome 17p13. The same chromosomal region is also frequently hypermethylated in cancer. Although loss of 17p13 has been often associated with p53 genetic alteration or Hypermethylated in Cancer 1 (HIC1) gene hypermethylation, other tumor suppressor genes (TSGs) located in this region have critical roles in tumorigenesis. A novel TSG mapping on human chromosome 17p13.2 is KCTD11REN (KCTD11). We have recently demonstrated that KCTD11 expression is frequently lost in human medulloblastoma (MB), in part by LOH and in part by uncharacterized epigenetic events. Using a panel of human 177 tumor samples and their normal matching samples representing 18 different types of cancer, we show here that the down-regulation of KCTD11 protein level is a specific and a diffusely common event in tumorigenesis. Additionally, in order to characterize the regulatory regions in KCTD11 promoter, we identified a CpG island and several Sp1 binding sites on this promoter, and demonstrated that Sp1 transcription factor and DNA methylation contribute, at least in part, to regulate KCTD11 expression. Our findings identify KCTD11 as a widely down-regulated gene in human cancers, and provide a basis to understand how its expression might be deregulated in tumor cells.

Show MeSH
Related in: MedlinePlus