PIAS1 Regulates Breast Tumorigenesis through Selective Epigenetic Gene Silencing

Liu, Bin; Tahk, Samuel; Yee, Kathleen M.; Yang, Randy; Yang, Yonghui; Mackie, Ryan; Hsu, Cary; Chernishof, Vasili; O’Brien, Neil A.; Jin, Yusheng; Fan, Guoping; Lane, Timothy F.; Rao, Jianyu; Slamon, Dennis J.; Shuai, Ke

doi:10.1371/journal.pone.0089464

Cited by 30 publications

(36 citation statements)

References 37 publications

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“…We noticed that PIAS1 W372A, which lacks SUMO E3 ligase activity, but retains the ability to bind to MYC (Figure 4A), neither up-regulates nor stabilizes MYC (Figure 4B, Figure S4A shows western blots and histogram summarizing the results of three independent experiments) (Liu et al, 2014a). Furthermore, PIAS1 affects only partially the half-life of the SUMO-deficient MYC K51/52R mutant (Figure 4C, Figure S4B shows western blots and histogram summarizing the results of three independent experiments).…”

Section: Resultsmentioning

confidence: 99%

PIAS1 Promotes Lymphomagenesis through MYC Upregulation

et al. 2016

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Summary The MYC proto-oncogene is a transcription factor implicated in a broad range of cancers. MYC is regulated by several post-translational modifications including SUMOylation, but the functional impact of this post-translational modification is still unclear. Here we report that the SUMO E3 ligase PIAS1 SUMOylates MYC. We demonstrate that PIAS1 promotes, in a SUMOylation-dependent manner, MYC phosphorylation at serine 62 and dephosphorylation at threonine 58. These events reduce the MYC turnover leading to increased transcriptional activity. Furthermore, we find that MYC is SUMOylated in primary B-cell lymphomas and that PIAS1 is required for the viability of MYC-dependent B-cell lymphoma cells as well as several cancer cell lines of epithelial origin. Finally, Pias1 null mice display endothelial defects reminiscent of Myc null mice. Taken together these results indicate that PIAS1 is a positive regulator of MYC.

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Section: Resultsmentioning

confidence: 99%

PIAS1 Promotes Lymphomagenesis through MYC Upregulation

et al. 2016

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“…Parallel experiments in a colorectal cancer cell line model and primary colon cancer isolates demonstrated that identical SUMO-sensitive pathways of gene regulation and physiologic response of tumor growth were present and functional. Our findings are in agreement with other studies showing that knockdown of the SUMO pathway enzymes UBC9 and SAE2 in colon cancer cells or PIAS1 in basal breast cancer reduced growth and inhibited tumorigenesis of xenografts (He et al., 2015, Liu et al., 2014). …”

Section: Discussionmentioning

confidence: 99%

“…Treatment of mice with anacardic acid inhibited the outgrowth of basal breast cancer xenografts, demonstrating the proof of principle that small-molecule SUMO inhibitors might form the basis of CSC-specific therapy (Bogachek et al., 2014, Bogachek et al., 2015b). Another recent study reported that knockdown of the SUMO enzyme PIAS1 repressed the TIC breast cancer population through epigenetic chromatin alterations resulting in gene silencing of cyclin D2, estrogen receptor, and WNT5A (Liu et al., 2014). Further studies have reported that knockdown of sumoylation enzymes impaired the outgrowth of colorectal cancer xenografts (He et al., 2015), suggesting the broad application of SUMO inhibitors in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas

et al. 2016

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SummaryMany solid cancers have an expanded CD44+/hi/CD24−/low cancer stem cell (CSC) population, which are relatively chemoresistant and drive recurrence and metastasis. Achieving a more durable response requires the development of therapies that specifically target CSCs. Recent evidence indicated that inhibiting the SUMO pathway repressed tumor growth and invasiveness, although the mechanism has yet to be clarified. Here, we demonstrate that inhibition of the SUMO pathway repressed MMP14 and CD44 with a concomitant reduction in cell invasiveness and functional loss of CSCs in basal breast cancer. Similar effects were demonstrated with a panel of E1 and E3 SUMO inhibitors. Identical results were obtained in a colorectal cancer cell line and primary colon cancer cells. In both breast and colon cancer, SUMO-unconjugated TFAP2A mediated the effects of SUMO inhibition. These data support the development of SUMO inhibitors as an approach to specifically target the CSC population in breast and colorectal cancer.

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“…prostate Overexpression of PIAS1 [122,123] Overexpression of PIAS3 [124] breast Overexpression of PIAS1 [125] Overexpression of PIAS3 [124] multiple myeloma Overexpression of PIAS1 [120] gastric Downregulation of PIAS3 [126] lung Overexpression of PIAS3 [124] brain Overexpression of PIAS3 [124] ovaries Expression of PIASγ correlates with cancer aggressiveness [127] pancreas Overexpression of PIASγ [128] RanBP2 small cell lung cancer Upregulation of RanBP2 compared to non-small cell lung cancer [129] leukemia Expressed as RanBP2-ALK fusion protein [130] SUMO proteases SENP1, SENP1, SENP2, SENP3, SENP5, SENP6, SENP7…”

Section: Figure 2 Sumoylation Of Important Cell Cycle Regulatorsmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

234

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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PIAS1 Regulates Breast Tumorigenesis through Selective Epigenetic Gene Silencing

Cited by 30 publications

References 37 publications

PIAS1 Promotes Lymphomagenesis through MYC Upregulation

PIAS1 Promotes Lymphomagenesis through MYC Upregulation

Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

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