Abstract：
:Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with poor prognosis. As transient and stable modifications to chromatin have emerged as critical mechanisms in oncogenic signaling, efforts to target epigenetic modifiers as a therapeutic strategy have accelerated in recent years. To identify chromatin modifiers that sustain tumor growth, we performed an epigenetic screen and found that inhibition of lysine methyltransferase G9a significantly affected the viability of ARMS cell lines. Targeting expression or activity of G9a reduced cellular proliferation and motility in vitro and tumor growth in vivo. Transcriptome and chromatin immunoprecipitation-sequencing analysis provided mechanistic evidence that the tumor-suppressor PTEN was a direct target gene of G9a. G9a repressed PTEN expression in a methyltransferase activity-dependent manner, resulting in increased AKT and RAC1 activity. Re-expression of constitutively active RAC1 in G9a-deficient tumor cells restored oncogenic phenotypes, demonstrating its critical functions downstream of G9a. Collectively, our study provides evidence for a G9a-dependent epigenetic program that regulates tumor growth and suggests targeting G9a as a therapeutic strategy in ARMS. SIGNIFICANCE: These findings demonstrate that RAC1 is an effector of G9a oncogenic functions and highlight the potential of G9a inhibitors in the treatment of ARMS.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Bhat AV,Palanichamy Kala M,Rao VK,Pignata L,Lim HJ,Suriyamurthy S,Chang KT,Lee VK,Guccione E,Taneja Rdoi
10.1158/0008-5472.CAN-18-2676subject
Has Abstractpub_date
2019-05-01 00:00:00pages
2232-2243issue
9eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-18-2676journal_volume
79pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract：:The long-term effects on mammary glands of 5beta-dihydrotestosterone, considered to be biologically inactive, were studied in female SHN mice with mammary tumor, virus. 5beta-Dihydrotestosterone was adminstered to mothers for 4 days from Day 12 to Day 15 of pregnancy (prenatal treatment) and to pups for 5 days of post...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1977-12-01 00:00:00
abstract：:Avian erythroblastosis virus strain R (AEV)-transformed, cloned erythroleukemia cells from three different ages of SC strain chickens were analyzed before and after differentiation induced by 1.0 mM butyric acid for expression of chicken fetal antigens (CFAs) and chicken adult antigens (CAAs) and for hemoglobin expres...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1982-11-01 00:00:00
abstract：:The base excision repair protein MED1 (also known as MBD4), an interactor with the mismatch repair protein MLH1, has a central role in the maintenance of genomic stability with dual functions in DNA damage response and repair. MED1 acts as a thymine and uracil DNA N-glycosylase on T:G and U:G mismatches that occur at ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-4488
更新日期：2006-08-01 00:00:00
abstract：:The MRP (multidrug resistance protein) gene, a member of the ubiquitous superfamily of ATP-binding cassette transporters, is associated with the multidrug resistance of mammalian cells to natural product anticancer agents. We have previously shown that abrogation of MRP expression by gene targeting leads to hypersensi...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1997-12-01 00:00:00
abstract：:Neoplasms in fish normally show poor abilities for metastasis, and there are no reports on intestinal cancer with metastasis to other organs. In aquaculture production, carnivorous salmonids in Northern Europe receive commercial feeds with plant ingredients. Such contents have been shown to cause chronic intestinal in...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-08-4877
更新日期：2009-05-15 00:00:00
abstract：:Thmidine (TdR) incorporation into DNA increased in the livers and spleens of rats bearing Yoshida sarcoma (solid type) or AH130 (solid type). TdR kinase and DNA polymerase activities increased in the serum, liver, and spleen of these rats, while thymidine monophosphate kinase activity increased appreciably only in the...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1975-03-01 00:00:00
abstract：:Ursodeoxycholic acid (UDCA) protects cells from the apoptotic effects of hydrophobic bile acids and some other cytotoxic agents. We observed the opposite result when assessing the effects of UDCA on the apoptotic response to mitochondrial photodamage induced by photodynamic therapy (PDT). Two photosensitizers with pre...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2000-12-15 00:00:00
abstract：:Estrogen exposure is considered a significant risk factor for breast cancer development. Estrogen receptor (ER) alpha is expressed at low levels in normal epithelia, and its expression is dramatically up-regulated as transformation progresses during mammary hyperplasia and adenocarcinoma development. The mechanism(s) ...
journal_title：Cancer research
pub_type： 杂志文章,评审
doi：10.1158/0008-5472.CAN-06-2805
更新日期：2006-11-15 00:00:00
abstract：:Cells that overexpress high-mobility group A1 (HMGA1) proteins exhibit deficient nucleotide excision repair (NER) after exposure to DNA-damaging agents, a condition ameliorated by artificially lowering intracellular levels of these nonhistone proteins. One possible mechanism for this NER inhibition is down-regulation ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-1689
更新日期：2007-07-01 00:00:00
abstract：:Loss of expression of the E-cadherin cell-cell adhesion molecule is important in carcinoma development and progression. Because previous data suggest that loss of E-cadherin expression in breast carcinoma may result from a dominant transcriptional repression pathway acting on the E-cadherin proximal promoter, we pursu...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2002-03-15 00:00:00
abstract：:We searched for potential suppressors of tumor metastasis by identifying the genes that are frequently down-regulated in hepatocellular carcinomas (HCC) while being negatively correlated with clinical parameters relevant to tumor metastasis, and we report here on the identification of N-myc downstream regulated gene 2...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-07-5040
更新日期：2008-06-01 00:00:00
abstract：:In vitro experiments selected optimal conditions to radiolabel with 131I the whole immunoglobulin and F(ab')2 fragments of the monoclonal antibody (MoAb) 225.28S to a high-molecular-weight melanoma-associated antigen (HMW-MAA). Injection of the radiolabeled whole immunoglobulin and F(ab')2 fragments of the MoAb 225.28...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1985-07-01 00:00:00
abstract：:A monoclonal antibody (5E8) has been used to identify and structurally characterize a previously unreported macromolecule present on the surface of human lung tumors. This antibody was derived from a hybrid clone that was produced using spleen cells of mice immunized with a surgically excised squamous cell carcinoma. ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1986-12-01 00:00:00
abstract：:The treatment of HL-60 promyelocytic leukemia cells with phorbol esters (12-O-tetradecanoylphorbol-13-acetate) results in the appearance of cell substrate adhesion and the release of a Mr 94,000 gelatin-degrading metalloprotease. The appearance of the metalloprotease in the culture medium directly correlates with the ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1990-02-15 00:00:00
abstract：:Cancer cells often fail to respond to stimuli that normally activate their intrinsic apoptotic machinery. Moreover, they are able to adapt to hypoxia by changing their glycolytic rate. Pyruvate kinase (PK) is a rate-limiting enzyme in glycolysis that is converted to a less active dimer form of PKM2 isoenzyme during on...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-2870
更新日期：2007-02-15 00:00:00
abstract：:During the last 2 yr more than 100 independent isolates of human T-cell leukemia virus type III have been obtained in this laboratory. Most isolates were from peripheral blood T-lymphocytes established in cell culture from acquired immunodeficiency syndrome (AIDS) and acquired immunodeficiency syndrome-related complex...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1985-09-01 00:00:00
abstract：:When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tum...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-18-1785
更新日期：2019-05-01 00:00:00
abstract：:PAX5 is a transcription factor essential for B-cell development. Recently, it has been found as a frequent target of aberrancies in childhood acute lymphoblastic leukemia (ALL; 30% of B cell ALL cases), showing monoallelic loss, point mutations, or chromosomal translocations. The role of these aberrancies is still poo...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-07-2778
更新日期：2008-01-01 00:00:00
abstract：:Local and metastatic relapses of prostate cancer often occur following attempted curative resection of the primary tumor, and up to 66% of local recurrences are associated with positive margins. Therefore, technologies that can improve the visualization of tumor margins and adjuvant therapies to ablate remaining tumor...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-19-0201
更新日期：2020-01-15 00:00:00
abstract：:Recently, we developed a nutritionally optimal medium for rapid clonal growth (greater than 1 population doubling/day) of normal human bronchial epithelial (NHBE) cells. Adding fetal bovine or adult human blood-derived serum to this medium depresses the clonal growth rate of NHBE cells in a dose-dependent fashion. In ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1983-12-01 00:00:00
abstract：:In a recent study, we showed that the plant alkaloid camptothecin (CPT) and its derivatives 9-nitro-CPT (9NC) and 9-amino-CPT (9AC) inhibit growth of both human melanocytes (MEL cells) and their malignant counterparts, malignant melanoma (BRO) cells in vitro. This growth inhibition was accompanied by an increase in th...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1994-02-01 00:00:00
abstract：:Epigenetic alterations of the genome such as DNA promoter methylation and chromatin remodeling play an important role in tumorigenesis. These modifications take place throughout development with subsequent events occurring later in adulthood. Recent studies, however, suggest that some epigenetic alterations that influ...
journal_title：Cancer research
pub_type： 杂志文章,评审
doi：10.1158/0008-5472.CAN-08-2184
更新日期：2008-11-15 00:00:00
abstract：:Copy number alterations are crucial for the development of colorectal cancer. Our whole-genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in colorectal cancer. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in colorectal canc...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-18-2986
更新日期：2019-07-01 00:00:00
abstract：:Micromolar concentrations of fecapentaene-12, a mutagen found in human feces, decrease survival measured as colony-forming efficiency and membrane integrity of cultured human fibroblasts. Fecapentaene-12 also decreases the content of cellular free low-molecular-weight thiols including glutathione. Fecapentaene-12 reac...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1989-11-01 00:00:00
abstract：:FGF2 signaling in glioblastoma induces resistance to radiotherapy, so targeting FGF2/FGFR pathways might offer a rational strategy for tumor radiosensitization. To investigate this possibility, we evaluated a specific role for FGFR1 in glioblastoma radioresistance as modeled by U87 and LN18 glioblastomas in mouse xeno...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-15-2058
更新日期：2016-05-15 00:00:00
abstract：:Two newly synthesized nitrosoureido sugars have been evaluated for their antitumor activity and diabetogenic potential in a number of in vitro and in vivo preclinical tumor model systems. 2-Amino-2-deoxy-N'-methyl-N'-nitrosoureido-1,3,4,6-tetra-O-acetyl-alpha- D- mannopyranose (MAZ), a lipophilic mannosamine derivativ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1985-02-01 00:00:00
abstract：:p21(Cip1) is a cyclin-dependent kinase inhibitor whose abundance increases in cells exposed to radiation or other DNA-damaging agents. Such increases activate a G1 checkpoint, which allows time for DNA repair before S phase entry. By inhibiting cell cycle progression, p21(Cip1) potentially suppresses tumorigenesis, an...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2003-06-15 00:00:00
abstract：:The INK4a/ARF locus encodes two distinct tumor suppressors, p16INK4a and p14ARF. Although the contribution of p16INK4a to human tumorigenesis through point mutation, deletion, and hypermethylation has been widely documented, little is known about specific p14ARF lesions and their consequences. Recent data indicate tha...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-04-01 00:00:00
abstract：:Breast cancer resistance protein (BCRP), also called ABCG2, confers resistance to anticancer agents such as 7-ethyl-10-hydroxycamptothecin (SN-38), mitoxantrone, and topotecan. We found previously that sulfated estrogens are physiologic substrates of BCRP. Flavonoids with weak estrogenic activities are called phytoest...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-04-0078
更新日期：2004-06-15 00:00:00
abstract：:The activity of an endonuclease(s) acting on double-stranded, ultraviolet-irradiated, and 2-acetylaminofluorene-bound DNA but not on double-stranded undamaged DNA triples within two hr after partial hepatectomy. Although the activity drops between four and six hr after operation, it remains above levels measured in li...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1981-06-01 00:00:00
