Systematic Interrogation of 3q26 Identifies <i>TLOC1</i> and <i>SKIL</i> as Cancer Drivers

Hägerstrand, Daniel; Tong, Alexander B.; Schumacher, Steven E.; Ilić, Nina; Shen, Rhine R.; Cheung, Hiu Wing; Vázquez, Francisca; Shrestha, Yashaswi; Kim, So Young; Giacomelli, Andrew O.; Rosenbluh, Joseph; Schinzel, Anna C.; Spardy, Nicole A.; Barbie, David A.; Mermel, Craig H.; Weir, Barbara A.; Garraway, Levi A.; Tamayo, Pablo; Mesirov, Jill P.; Beroukhim, Rameen; Hahn, William C.

doi:10.1158/2159-8290.cd-12-0592

Cited by 74 publications

(71 citation statements)

References 49 publications

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“…The same study also found that SMAD4 knockdown increased the invasiveness of human mammary epithelial cells, while SKIL overexpression had no effect on cell growth, in agreement with our findings [28]. Another recent study has proposed that SKIL can interact with and promote the activity of estrogen receptor α in the nuclei of breast carcinoma cells.…”

Section: Discussionsupporting

confidence: 91%

“…Overexpression of either SKI or SKIL in chicken embryo fibroblasts is sufficient to induce oncogenic transformation [26], and SKIL expression is elevated in many human cancers, including cancers of the skin, breast, colon and blood [27]. The 3q26 locus is amplified in several cancer types, and SKIL (along with TLOC1 ) has been highlighted as the most potent oncogene in this region [28]. Both SKI and SKIL contain an 80 aa SAND-like domain that can bind with the MH2 domain of SMAD4 [29].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the inhibitory role of SKIL on TGF-β signaling, a recent study has proposed that SKIL may play a role in regulating epithelial-to-mesenchymal transition (EMT) by inducing expression of SNAI2 (SLUG), a master regulator of EMT [28]. The same study also found that SMAD4 knockdown increased the invasiveness of human mammary epithelial cells, while SKIL overexpression had no effect on cell growth, in agreement with our findings [28].…”

Section: Discussionmentioning

confidence: 99%

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Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer

et al. 2015

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Prostate cancer is the third most common cause of male cancer death in developed countries, and one of the most comprehensively characterized human cancers. Roughly 60% of prostate cancers harbor gene fusions that juxtapose ETS-family transcription factors with androgen regulated promoters. A second subtype, characterized by SPINK1 overexpression, accounts for 15% of prostate cancers. Here we report the discovery of a new prostate cancer subtype characterized by rearrangements juxtaposing the SMAD inhibitor SKIL with androgen regulated promoters, leading to increased SKIL expression. SKIL fusions were found in 6 of 540 (1.1%) prostate cancers and 1 of 27 (3.7%) cell lines and xenografts. 6 of 7 SKIL-positive cancers were negative for ETS overexpression, suggesting mutual exclusivity with ETS fusions. SKIL knockdown led to growth arrest in PC-3 and LNCaP cell line models of prostate cancer, and its overexpression led to increased invasiveness in RWPE-1 cells. The role of SKIL as a prostate cancer oncogene lends support to recent studies on the role of TGF-β signaling as a rate-limiting step in prostate cancer progression. Our findings highlight SKIL as an oncogene and potential therapeutic target in 1-2% of prostate cancers, amounting to an estimated 10,000 cancer diagnoses per year worldwide.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer

et al. 2015

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“…Only one coding gene, SEC62 (also named TLOC1), showed two circular RNAs that differed in terms of number of the exons involved. These two circRNAs were located in the chromosome region 3q26.2, that it is interestingly frequent amplified in several cancers [21]. The longest in terms of nucleotides (11414 nts) was the hsa-circ-0001358 (alias hsa-circ-001803), while the second was hsa-circ-0122662, 8920 nts long.…”

Section: Resultsmentioning

confidence: 99%

Profiling of the Predicted Circular RNAs in Ductal In Situ and Invasive Breast Cancer: A Pilot Study

Galasso

Costantino

Pasquali

et al. 2016

International Journal of Genomics

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The recent advantage obtained by next generation sequencing allows a depth investigation of a new “old” kind of noncoding transcript, the circular RNAs. Circular RNAs are nontranslated RNAs, typically nonpolyadenylated, with a resistance to exonucleases that gives them the ability to be more stable than the common linear RNA isoforms. We used a bioinformatic detection tool (CIRCexplorer) to research predictive circRNAs from the next generation sequenced data of five samples of ductal in situ carcinoma (DCIS) and matched adjacent invasive ductal carcinoma (IDC). Furthermore, we also investigated the circular RNAs expressed in MCF7, an invasive breast ductal carcinoma cell line. We described the genomic context of the predicted circular RNAs and we address the hypothetical possible functional roles. This study showed a perspective of a panel of predictive circRNAs identified and the function that circRNAs could exert.

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“…A possible exception may be the 3q26 amplicon. Indeed, the 3q26 locus is frequently amplified in various types of cancer (ovarian, breast, and non-small cell lung cancers) and is correlated with poor prognosis and an invasive phenotype (41,42). PLD1 was identified as a resident gene in the minimal common amplified region of 3q26 (42).…”

Section: Genomic Alternation Of Pld1 Gene In Cancermentioning

confidence: 99%

Functional Regulation of Phospholipase D Expression in Cancer and Inflammation

Kang

Choi

Min

2014

Journal of Biological Chemistry

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Phospholipase D (PLD) regulates downstream effectors by generating phosphatidic acid. Growing links of dysregulation of PLD to human disease have spurred interest in therapeutics that target its function. Aberrant PLD expression has been identified in multiple facets of complex pathological states, including cancer and inflammatory diseases. Thus, it is important to understand how the signaling network of PLD expression is regulated and contributes to progression of these diseases. Interestingly, small molecule PLD inhibitors can suppress PLD expression as well as enzymatic activity of PLD and have been shown to be effective in pathological mice models, suggesting the potential for use of PLD inhibitors as therapeutics against cancer and inflammation. Here, we summarize recent scientific developments regarding the regulation of PLD expression and its role in cancer and inflammatory processes.Phospholipase D produces phosphatidic acid (PA) 2 via hydrolysis of phospholipids such as phosphatidylcholine and cardiolipin. As a lipid second messenger, PA has been implicated in a wide range of pathophysiological processes including proliferation, oncogenesis, inflammation, phagocytosis, membrane fusion, and spermatogenesis. Phosphatidylcholine-specific PLD1 and PLD2 are the classic mammalian isoforms of PLD (1, 2). Growth factor, mitogen, and inflammatory cytokines up-regulate expression and activity of PLD; however, aberrant dysregulation of PLD occurs in various cancers and inflammation-related diseases. Accordingly, it is important to understand how expression of PLD is regulated and contributes to these diseases.An association between inflammation and cancer has been observed (3) and supported by recent epidemiological data that indicated ϳ20% of cancer deaths are linked to chronic infections and persistent inflammation (4). The PLD signaling pathway provides a possible molecular link between inflammation and cancer; however, systematic investigation of PLD as a therapeutic target has only begun within the last few years with the development of small molecule PLD inhibitors and PLD knock-out mice (5-13). This review covers recent advances in the regulation of PLD expression and its role in cancer and inflammation.

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Systematic Interrogation of 3q26 Identifies TLOC1 and SKIL as Cancer Drivers

Cited by 74 publications

References 49 publications

Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer

Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer

Profiling of the Predicted Circular RNAs in Ductal In Situ and Invasive Breast Cancer: A Pilot Study

Functional Regulation of Phospholipase D Expression in Cancer and Inflammation

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