Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/−clear cell renal carcinoma

Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of theVHLtumor suppressor gene. TheVHLgene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of thePBRM1andBAP1tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC.PBRM1encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature.

Download Full-text

URINARY BLADDER TRANSITIONAL CELL CARCINOGENESIS IS ASSOCIATED WITH DOWN-REGULATION OF NF1 TUMOR SUPPRESSOR GENE IN VIVO AND IN VITRO

The Journal of Urology ◽

10.1097/00005392-199904010-00469 ◽

1999 ◽

pp. 117

Author(s):

Vesa A. Aaltonen ◽

Peter J. Bostrom ◽

Karl-Ove Soderstrom ◽

Outi Hirvonen ◽

Juha Tuukkanen ◽

...

Keyword(s):

Tumor Suppressor ◽

Urinary Bladder ◽

Tumor Suppressor Gene ◽

Transitional Cell ◽

Suppressor Gene ◽

Down Regulation

Download Full-text

Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

American Journal Of Pathology ◽

10.1016/s0002-9440(10)65322-9 ◽

1999 ◽

Vol 154 (3) ◽

pp. 755-765 ◽

Cited By ~ 25

Author(s):

Vesa Aaltonen ◽

Peter J. Boström ◽

Karl-Ove Söderström ◽

Outi Hirvonen ◽

Juha Tuukkanen ◽

...

Keyword(s):

Tumor Suppressor ◽

Urinary Bladder ◽

Tumor Suppressor Gene ◽

Transitional Cell ◽

Suppressor Gene ◽

Down Regulation

Download Full-text

In Vitro and In Vivo Effects of Tumor Suppressor Gene PTEN on Endometriosis: An Experimental Study

Medical Science Monitor ◽

10.12659/msm.901091 ◽

2016 ◽

Vol 22 ◽

pp. 3727-3736 ◽

Cited By ~ 10

Author(s):

Juan Lv ◽

Qiaoying Zhu ◽

Xuemei Jia ◽

Ningzhu Yu ◽

Qian Li

Keyword(s):

Experimental Study ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

In Vivo Effects

Download Full-text

ECRG4 as a novel tumor suppressor gene inhibits colorectal cancer cell growth in vitro and in vivo

Tumor Biology ◽

10.1007/s13277-015-4775-2 ◽

2016 ◽

Vol 37 (7) ◽

pp. 9111-9120 ◽

Cited By ~ 11

Author(s):

Zhengxu Cai ◽

Pin Liang ◽

Jize Xuan ◽

Jiajia Wan ◽

Huishu Guo

Keyword(s):

Colorectal Cancer ◽

Cell Growth ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Cancer Cell ◽

Suppressor Gene ◽

Colorectal Cancer Cell ◽

Cancer Cell Growth

Download Full-text

The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 α (HIF-1α) activity: involvement in myeloma-induced angiogenesis

Blood ◽

10.1182/blood-2007-02-074617 ◽

2007 ◽

Vol 110 (13) ◽

pp. 4464-4475 ◽

Cited By ~ 83

Author(s):

Simona Colla ◽

Sara Tagliaferri ◽

Francesca Morandi ◽

Paolo Lunghi ◽

Gaetano Donofrio ◽

...

Keyword(s):

Tumor Suppressor ◽

Family Member ◽

Tumor Suppressor Gene ◽

Molecular Mechanisms ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Direct Interaction ◽

Suppressor Gene

Angiogenesis has a critical role in the pathophysiology of multiple myeloma (MM); however, the molecular mechanisms underlying this process are not completely elucidated. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) has been recently implicated in solid tumors as a repressor of angiogenesis. In this study, we found that ING4 expression in MM cells was correlated with the expression of the proangiogenic molecules interleukin-8 (IL-8) and osteopontin (OPN). Moreover, we demonstrate that ING4 suppression in MM cells up-regulated IL-8 and OPN, increasing the hypoxia inducible factor-1α (HIF-1α) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1α by siRNA suppressed IL-8 and OPN production by MM cells under hypoxia. A direct interaction between ING4 and the HIF prolyl hydroxylase 2 (HPH-2) was also demonstrated. Finally, we show that ING4 suppression in MM cells significantly increased vessel formation in vitro, blunted by blocking IL-8 or OPN. These in vitro observations were confirmed in vivo by finding that MM patients with high IL-8 production and microvascular density (MVD) have significantly lower ING4 levels compared with those with low IL-8 and MVD. Our data indicate that ING4 exerts an inhibitory effect on the production of proangiogenic molecules and consequently on MM-induced angiogenesis.

Download Full-text

Hypermethylation of heparanase 2 promotes colorectal cancer proliferation and is associated with poor prognosis

Journal of Translational Medicine ◽

10.1186/s12967-021-02770-0 ◽

2021 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Hui Zhang ◽

Chenxin Xu ◽

Chen Shi ◽

Junying Zhang ◽

Ting Qian ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Promoter Methylation ◽

Genomic Analysis ◽

Promoter Hypermethylation ◽

Suppressor Gene ◽

The Cancer Genome Atlas

Abstract Background The epigenetic abnormality of tumor-associated genes contributes to the pathogenesis of colorectal carcinoma (CRC). However, methylation in colorectal cancer is still poorly characterized. Method By integration of DNA methylation data from the GEO database and gene expression data from The Cancer Genome Atlas database, the aberrantly methylated genes involved in CRC tumorigenesis were identified. Subsequent in vitro experiments further validated their role in CRC. Results We performed integrative genomic analysis and identified HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. K-M survival analysis showed that hypermethylation–low expression of heparanase 2 (HPSE2) was related to poor patient prognosis. Overexpression of HPSE2 reduced cell proliferation in vivo and in vitro. HPSE2 could regulate the p53 signaling pathway to block the cell cycle in G1 phase. Conclusion HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. HPSE2 performs a tumor suppressive function by activating the p53/ p21 signaling cascade. The promoter hypermethylation of HPSE2 is a potential therapeutic target in patients with CRC, especially those with late-stage CRC.

Download Full-text

Loss-Of-Function Mutation Of ARID1A Tumor Suppressor Gene In A Glycogen-Rich Clear Cell Mammary Carcinoma

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.319 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S146-S146

Author(s):

C A De la Sancha Verduzco ◽

N Popnikolov ◽

R Ruiz-Cordero

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Molecular Mechanisms ◽

Clear Cell ◽

Suppressor Gene ◽

Genetic Alterations ◽

Chromosome 1 ◽

Loss Of Function ◽

Truncating Mutation ◽

Molecular Studies

Abstract Introduction/Objective Glycogen-rich clear cell carcinoma (GRCC-CA) is a rare subtype of breast carcinoma accounting for 0.9 - 3% of all breast malignancies. It is characterized by more than 90% of the neoplastic cells containing glycogen-abundant clear cytoplasm. Due to the rarity of this tumor, the information about the specific genetic alterations, their prognostic significance and potential therapeutic implications are quite limited. Here we report the molecular alterations of a GRCC-CA diagnosed in a 69-year-old woman. Methods Tumor-only sequencing using a hybrid-capture next-generation sequencing (HC-NGS) assay was performed using formalin-fixed paraffin-embedded tissue. The HC-NGS panel included the coding regions of 479 cancer-related genes, select introns of 47 genes and the TERT promoter. Results The HC-NGS showed the following alterations: 1) large inversion in chromosome 1 between exon 20 of gene ARID1A (1p36.12) and intron 2 of KDM5B (1q32.1) leading to loss-of-function of ARID1A tumor suppressor gene, 2) MAP2K4 p.E376 truncating mutation with a variant allelic frequency of 87% suggestive of loss-of-heterozygosity, 3) c- MYC gene amplification (5x), 4) variant of uncertain significance in gene PTPRB (p.D1848N) and 5) deep deletions of NCKAP5, CCNT2, MAP3K19, LRP1B, and KMT2A genes. Conclusion We report for the first time a loss-of-function mutation of ARID1A gene in mammary GRCC-CA. Loss of function of ARID1A gene, as shown by molecular studies or loss of protein expression, is often seen in clear cell carcinomas with high glycogen contents from other sites (ovary and kidney), indicating similarities in the molecular mechanisms of development. In our patient, the loss of ARID1A probably enhanced the effect of the c-MYC amplification, since ARID1A is involved in the repression of c-MYC and other proliferation associated genes during differentiation. Larger molecular studies are needed to elucidate further the genetic mechanisms of mammary GRCC- CA.

Download Full-text

MIR99AHG is a noncoding tumor suppressor gene in lung adenocarcinoma

Cell Death and Disease ◽

10.1038/s41419-021-03715-7 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Chencheng Han ◽

Hong Li ◽

Zhifei Ma ◽

Guozhang Dong ◽

Qianyun Wang ◽

...

Keyword(s):

Tumor Suppressor ◽

Lung Adenocarcinoma ◽

Tumor Suppressor Gene ◽

Copy Number ◽

Mammalian Target Of Rapamycin ◽

Suppressor Gene ◽

Bioinformatics Analyses ◽

Vesicle Biogenesis

AbstractLittle is known about noncoding tumor suppressor genes. An effective way to identify these genes is by analyzing somatic copy number variation (CNV)-related noncoding genes. By integrated bioinformatics analyses of differentially expressed long noncoding RNAs (lncRNAs) and arm-level CNVs in lung adenocarcinoma (LUAD), we identified a potential antitumor gene, MIR99AHG, encoding lncRNA MIR99AHG as well as a miR-99a/let-7c/miR-125b2 cluster on chromosome 21q. All four of these transcripts were downregulated in LUAD tissues partly due to the copy number deletion of the MIR99AHG gene. Both MIR99AHG and miR-99a expression was positively correlated with the survival of LUAD patients. MIR99AHG suppressed proliferation and metastasis and promoted autophagy both in vitro and in vivo. Mechanistically, the interaction between MIR99AHG and ANXA2 could accelerate the ANXA2-induced ATG16L+ vesicle biogenesis, thus promoting phagophore assembly. Additionally, miR-99a targeted a well-known autophagy suppressor, mammalian target of rapamycin (mTOR), thereby synergistically promoting autophagy and postponing LUAD progression with MIR99AHG. In summary, MIR99AHG emerges as a noncoding tumor suppressor gene in LUAD, providing a new strategy for antitumor therapy.

Download Full-text

In Vitro and In Vivo Evidence That TSC-22 Is a Putative Tumor Suppressor Gene in Primary Murine and Human Leukemia.

Blood ◽

10.1182/blood.v108.11.2211.2211 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2211-2211

Author(s):

Jianhua Yu ◽

Li Yu ◽

Bjoern Hackanson ◽

Min Wei ◽

Zachary Boyd ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Cell Lines ◽

Suppressor Gene ◽

Proximal Promoter ◽

Human Leukemia ◽

Putative Tumor Suppressor Gene ◽

Putative Tumor Suppressor

Abstract Transforming growth factor-β-stimulated clone-22 (TSC-22) is a gene that has been shown to be silenced in brain and prostate cancer, but its function and the mechanism responsible for this silencing are unknown. We used our model of spontaneous T-natural killer (NK) acute lymphoblastic leukemia (ALL) and discovered that the TSC-22 promoter was methylated resulting in absent expression in seven of eight cases of primary NK-T ALL, but not in cells from normal mice or mice with polyclonal expansion of T and NK cells. We found that TSC-22 was undetectable or minimally expressed in mouse lymphoma cell lines YAC-1 and EL-4 and human leukemia cell lines Jurkat and RPMI 8866, but treatment with the demethylation agent 5-aza-2′-deoxycytidine restored or increased TSC-22 expression. We mapped the TSC-22 promoter and discovered a CPG island in the proximal region and determined that its methylation was responsible for the decreased gene expression. Over-expression of TSC-22 slowed in vitro cell growth and resulted in a dramatic decrease of tumor size in vivo. Finally, TSC-22 expression was found to be absent or substantially reduced in human chronic lymphocytic leukemia and acute myeloid leukemia compared to normal human tissue. Collectively, our data indicate that TSC-22 is silenced via DNA methylation within its proximal promoter, and this silencing appears to contribute to its function as a putative tumor suppressor gene in leukemia. Silencing of TSC-22 can be reversed by 5-aza-2′-deoxycytidine, recently approved by the FDA for the treatment of myelodysplastic syndrome.

Download Full-text