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  • American Association for Cancer Research (AACR)  (3)
  • 1
    Online Resource
    Online Resource
    VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Discovery Vol. 7, No. 11 ( 2017-11-01), p. 1284-1305
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    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 7, No. 11 ( 2017-11-01), p. 1284-1305
    Abstract: Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel–Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α–HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter–enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter–enhancer complexes. Cancer Discov; 7(11); 1284–305. ©2017 AACR. See related commentary by Ricketts and Linehan, p. 1221. This article is highlighted in the In This Issue feature, p. 1201
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-17-0375
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2607892-2
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  • 2
    Online Resource
    Online Resource
    PDK1 Signaling Toward PLK1–MYC Activation Confers Oncogenic Transformation, Tumor-Initiating Cell Activation, and Resistance to mTOR-Targeted Therapy
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Discovery Vol. 3, No. 10 ( 2013-10-01), p. 1156-1171
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    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 3, No. 10 ( 2013-10-01), p. 1156-1171
    Abstract: Although 3-phosphoinositide–dependent protein kinase-1 (PDK1) has been predominately linked to the phosphoinositide 3-kinase (PI3K)–AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1–PLK1–MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency. Intriguingly, PDK1–PLK1–MYC signaling induces an embryonic stem cell–like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self-renewal. Finally, we show that a PLK1 inhibitor synergizes with an mTOR inhibitor to induce synergistic antitumor effects in colorectal cancer by antagonizing compensatory MYC induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting MYC-associated tumorigenesis and therapeutic resistance. Significance: This work identifies PDK1–PLK1–MYC signaling as a new oncogenic pathway driving oncogenic transformation and CSC self-renewal. Targeted inhibition of PDK1/PLK1 is robust in targeting MYC dependency in cancer cells. Thus, our findings provide important insights into cancer and CSC biology and have significant therapeutic implications. Cancer Discov; 3(10); 1156–71. ©2013 AACR. See related commentary by Cunningham and Ruggero, p. 1099 This article is highlighted in the In This Issue feature, p. 1083
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-12-0595
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2607892-2
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  • 3
    Online Resource
    Online Resource
    Abstract 1494: PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in clear cell renal cell carcinoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1494-1494
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1494-1494
    Abstract: PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and the inactivation of PBRM1 is the second most frequent mutational event in kidney tumorigenesis. However, the impact of PBRM1 loss on chromatin remodeling, especially pertaining to kidney tumorigenesis, has not been examined previously. Here we show that in VHL-deficient ccRCC tumors, PBRM1 deficiency results in altered PBAF complexes that retain the association between SMARCA4 and ARID2 but disengage BRD7 from SMARCA4. The PBRM1-deficient PBAF complexes redistribute from promoter proximal regions to distal enhancer regions containing motifs of pro-tumorigenic factors including NF-κB. Subsequently, PBRM1-deficient cells display heightened NF-κB activity across multiple cell models. The ATPase function of SMARCA4 maintains chromatin occupancy of both pre-existing and newly acquired RELA specific to PBRM1 loss, and activates downstream target gene expression. Proteasome inhibitor bortezomib reverses NF-κB activation by reducing RELA occupancy and delays growth of PBRM1-deficient tumors. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes. Citation Format: Xiaosai Yao, Jing Han Hong, Amrita Nargund, Michelle Shu Wen Ng, Hong Lee Heng, Zhimei Li, Peiyong Guan, Masahiro Sugiura, Pek Lim Chu, Loo Chien Wang, Xiaofen Ye, Robert Yauch, Kenneth Tou-En Chang, Radoslaw M. Sobota, Patrick Tan, Bin Tean Teh. PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1494.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-1494
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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