Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

Ahmed, Kazi Mokim; Tsai, Connie Y.; Lee, Wen‐Hwa

doi:10.1074/jbc.m109.062265

Cited by 44 publications

(48 citation statements)

References 42 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A group of genes have been identified to be tentatively regulated by ZBRK1 (25). Among these, GADD45A, Angiopoietin 1, and high mobility group AT-hook 2 have been shown to be regulated by ZBRK1 through interaction with the BRCA1⅐CtIP complex (27,28,32). In addition, our preliminary results showed that constitutive exogenous expression of ZBRK1 had no effect on the activation of cell cycle arrest and apoptosis in HeLa and U2OS cells, suggesting that transcriptional activation of genes essential for growth arrest or cell death are dependent on ZBRK1 repression.…”

Section: Discussionmentioning

confidence: 99%

“…ZBRK1 thus represents the first KRAP zinc finger protein (KRAB-ZFP) harboring two independent repression domains. ZBRK1 association with BRCA1 and CtIP repress transcription of Angiopoietin 1 (27) and high mobility group AT-hook 2 (28). The same repressor complex can also regulate the DNA damage response gene GADD45A for the maintenance of genomic integrity (29 -31).…”

mentioning

confidence: 99%

See 1 more Smart Citation

RB·E2F1 Complex Mediates DNA Damage Responses through Transcriptional Regulation of ZBRK1*

Liao

Tsai

Chang

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

RB plays an essential role in DNA damage-induced growth arrest and regulates the expression of several factors essential for DNA repair machinery. However, how RB coordinates DNA damage response through transcriptional regulation of genes involved in growth arrest remains largely unexplored. We examined whether RB can mediate the response to DNA damage through modulation of ZBRK1, a zinc finger-containing transcriptional repressor that can modulate the expression of GADD45A, a DNA damage response gene, to induce cell cycle arrest in response to DNA damage. We found that the ZBRK1 promoter contains an authentic E2F-recognition sequence that specifically binds E2F1, but not E2F4 or E2F6, together with chromatin remodeling proteins CtIP and CtBP to form a repression complex that suppresses ZBRK1 transcription. Furthermore, loss of RB-mediated transcriptional repression led to an increase in ZBRK1 transcript levels, correlating with increased sensitivity to ultraviolet (UV) and methyl methanesulfonate-induced DNA damage. Taken together, these results suggest that the RB⅐CtIP (CtBP interacting protein)/CtBP (C terminus-binding protein) /E2F1 complex plays a critical role in ZBRK1 transcriptional repression, and loss of this repression may contribute to cellular sensitivity of DNA damage, ultimately leading to carcinogenesis.The DNA damage response that responds to genotoxic stress induced by radiation, chemicals, and endogenous reactive oxygen species is highly conserved in higher eukaryotes (1, 2). The cellular responses to DNA damage include activation of cell-cycle arrest, apoptosis, and DNA damage repair (3). In mammals, multiple partially overlapping DNA repair mechanisms, including base excision, recombination, and mismatch repair, are required for proper DNA damage repair. Defects in these repair pathways frequently lead to irreparable DNA damage, aging, and cancer.RB, a prototypic tumor suppressor (4), is essential for regulating cell cycle progression through interaction with binding partners such as E2F (5). In quiescent and early G 1 cells, RB associates with the E2F family of transcription factors to repress the expression of E2F-responsive genes involved in cell cycle progression (6). As cells progress toward S-phase, RB is phosphorylated by cyclin-dependent kinases, releasing E2F, which opens the DNA replication origin, and induces transcription of S-phase genes (7). When RB is lost or inactivated, DNA replication origins become readily accessible, resulting in uncontrolled transcription of S-phase genes and ultimately leading to premature S-phase progression (8). RB also plays an essential role in DNA damage-induced growth arrest (9) and transcriptional regulation of several DNA damage-repair factors involved in the ultraviolet (UV) damage repair process, including FEN1, XPC, RPA2-3, RFC4, and proliferating cell nuclear antigen (10). Although previous studies have established that phosphorylation of RB inactivates its binding activity with its interacting partners and promotes cell cycle progression (1...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

RB·E2F1 Complex Mediates DNA Damage Responses through Transcriptional Regulation of ZBRK1*

Liao

Tsai

Chang

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…We found that MIR182 repression of BRCA1 expression will release a negative regulation and result in HMGA2 overexpression. 11,25 We propose that MIR182 overexpression in high-grade serous ovarian carcinoma may be in part or completely responsible for HMGA2 overexpression. Although MIR182 and HMGA2 overexpression are found in nearly 70% of high-grade serous ovarian carcinoma (this study and Mahajan et al 16 and Wei et al 17 ), low correlation of expression of these two genes was found (r ¼ 0.23) in this study.…”

Section: Discussionmentioning

confidence: 96%

“…16,17 The major tumorigenic functions of HMGA2 in the pathogenesis of high-grade serous ovarian carcinoma likely include regulation of epithelial mesenchymal transition. 24 A study by Ahmed et al 25 shows that BRCA1, ZBRK1 and CtIP form a repression complex that coordinately inhibits HMGA2 expression via a ZBRK1 recognition site in the HMGA2 promoter. We found that MIR182 repression of BRCA1 expression will release a negative regulation and result in HMGA2 overexpression.…”

Section: Discussionmentioning

confidence: 99%

Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

et al. 2012

View full text Add to dashboard Cite

BRCA1/BRCA2 mutations are common and the hallmarks of high-grade serous ovarian carcinoma. We found that MIR182, a negative BRCA1 regulator, is significantly overexpressed in high-grade serous ovarian carcinoma. To examine whether overexpression of MIR182 and its target genes, including BRCA1, HMGA2 (high-mobility group A2), FOXO3 and MTSS1, are associated with high-grade serous ovarian carcinoma tumor types and clinical outcome, we studied MIR182 by in situ hybridization and its target gene expression by immunohistochemistry in 117 cases of advanced ovarian cancer. We found that high-grade serous ovarian carcinoma had significantly higher MIR182 (P ¼ 0.0003) and HMGA2 (P ¼ 0.04) expression, and significantly lower BRCA1 (Po0.0001) and FOXO3 (Po0.001) expression than normal controls. MIR182 is significantly correlated with MTSS1 expression (r ¼ 0.31; Po0.001), whereas other target genes did not show a significant correlation with MIR182, indicating a complicated regulatory mechanisms of these genes in high-grade serous ovarian carcinoma. Among the examined MIR182 target genes, only HMGA2 was significantly associated with serous type carcinomas (Po0.01), ascites (Po0.01) and high death rate (P ¼ 0.02). FOXO3 expression was associated with lower-stage disease (P ¼ 0.04) and solid growth pattern (P ¼ 0.03). MIR182 expression is significantly higher in high-grade serous ovarian carcinoma than in fallopian tubes. Modern Pathology (2012) 25, 1644-1653; doi:10.1038/modpathol.2012.118; published online 13 July 2012Keywords: miR-182; ovarian cancer; BRCA1; HMGA2; MTSS1 High-grade serous ovarian carcinoma is an aggressive and deadly form of ovarian cancer, yet its pathogenesis is poorly understood. Despite significant efforts of clinical researchers, the survival rate of women with high-grade serous ovarian carcinoma has not changed in the past 50 years. 1 These tumors are often high-grade and aggressive at presentation, with a poor prognosis. Recent recognition of the existence of high-grade serous ovarian carcinoma precursor lesions, serous tubal intraepithelial carcinoma, 2,3 in the distal (fimbriated) ends of the fallopian tubes has renewed hope that we will be able to identify early tumorigenic events leading to high-grade serous ovarian carcinoma and reveal new opportunities for early detection and treatment that may decrease the mortality rate among women with this cancer.BRCA1 and BRCA2 mutations are a hallmark of high-grade serous ovarian carcinoma tumorigenesis. 4 Women with germline BRCA1/2 mutations have a 30-70% chance of developing high-grade serous ovarian carcinoma by age 70. 5 Germline BRCA mutations, 6 somatic mutations and epigenetic inactivation of BRCA1/2 (via methylation) can be found in nearly 30% of high-grade serous ovarian carcinoma cases. 7 BRCA1 has a broader role upstream of BRCA2, participating in various cellular

show abstract

“…It is reported that HMGA2 binds the complex formed by pRB and HDAC1 to dissociate pRB from genomic promoter regions and promotes the transcriptional activity of E2F1 and blocks the G1/S transition to inhibit the cell proliferation (22). It has been discovered that HMGA2 is upregulated in many benign and malignant tumors, such as colorectal, breast, pancreatic, ovarian, and lung cancer (25)(26)(27)(28). In the present study, it was found that the mRNA and protein levels of HMGA2 were often upregulated in GBC tissues.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-26a acts as a tumor suppressor inhibiting gallbladder cancer cell proliferation by directly targeting HMGA2

Zhou

Guo

Zhao

et al. 2014

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. MicroRNAs (miRNAs) are a class of small, single-stranded, non-coding RNA molecules which can act as oncogenes or tumor suppressor genes in human cancer. However, the possible functions and mechanisms of miRNA action in gallbladder cancer (GBC) have not been elucidated. In the present study, it was found that miR-26a was often downregulated in GBC and the expression of miR-26a was associated with neoplasm histological grade. miR-26a significantly inhibited the proliferation of GBC cells based on the gain-of-function assays. Furthermore, we demonstrated that high mobility group AT-hook 2 (HMGA2) was a direct target of miR-26a. The results showed that HMGA2 mRNA levels and miR-26a levels were negatively correlated. In addition, we confirmed that reintroduction of HMGA2 antagonized the inhibition of miR-26a to GBC cell proliferation and all these effects were achieved through the cell cycle. Together, all these results suggest that miR-26a expression contributes to GBC proliferation by targeting HMGA2. miR-26a shows promise as a prognosis factor and therapeutic target of GBC patients. IntroductionMicroRNAs (miRNAs) are a class of small, endogenous, noncoding RNAs which act as post-trancriptional regulators via binding to the 3' untranslated regions (3'-UTRs) of the target gene mRNA, and have vital functions in many of physiological and pathological processes, as well as in carcinogenesis (1-5). It has been reported that miRNAs can act as oncogene or tumor suppressor gene in various cancers, including lung, colorectal, and liver cancer (6,7).Gallbladder cancer (GBC) with poor prognosis is one of the most prevalent and aggressive malignant types of cancer in China. GBC is the tenth most common cancer in Shanghai and the average survival of patients is ~9 months (8). Many patients have no chance to accept radical operation when they are diagnosed. Despite its poor prognosis and high morbidity, the miRNA function in GBC remains largely unknown.The miRNA microarray assays performed on 4 pairs of GBC and paracancerous tissues, revealed that miR-26a is significantly downregulated in GBC tissues. It has been reported that miR-26a was downregulated in pancreatic, nasopharyngeal, breast and lung cancer, and miR-26a can acts as tumor suppressor gene via directly targeting enhancer of Zeste homolog 2 (EZH2) (9-12). Also in hepatocellular carcinoma cells, miR-26a can inhibit cell proliferation by regulating cyclin D2,14). It has been demonstrated that expression levels of miR-26a are lower in the tumors of renal cell carcinoma patients who developed tumor relapse, moreover, the lowest levels of miR-26a are observed in primary metastatic tumors (15). These findings suggested that miR-26a might play a vital role in GBC physiological and pathological processes.In the present study, we demonstrated that miR-26a is significantly downregulated in GBC tissues compared with paracancerous tissues and miR-26a is closely correlated with the histologic grade of the neoplasm. Enforced, highly expressed miR-26a was able to inhibit G...

show abstract

Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

Cited by 44 publications

References 42 publications

RB·E2F1 Complex Mediates DNA Damage Responses through Transcriptional Regulation of ZBRK1*

RB·E2F1 Complex Mediates DNA Damage Responses through Transcriptional Regulation of ZBRK1*

Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

MicroRNA-26a acts as a tumor suppressor inhibiting gallbladder cancer cell proliferation by directly targeting HMGA2

Contact Info

Product

Resources

About