Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma

Hoellein, Alexander; Fallahi, Mohammad; Schoeffmann, Stephanie; Steidle, Sabine; Schaub, Franz X.; Rudelius, Martina; Laitinen, Iina; Nilsson, Lisa M.; Goga, Andrei; Peschel, Christian; Nilsson, Jonas A.; Cleveland, John L.; Keller, Ulrich

doi:10.1182/blood-2014-06-584524

Cited by 79 publications

(97 citation statements)

References 58 publications

(85 reference statements)

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“…We found that PIAS1 and MYC are barely expressed in resting B-cells; however, both PIAS1 and MYC are readily detectable in B-cells after stimulation with LPS or with LPS and Interleukin 4 (IL4) (Hoellein et al, 2014; Sakurai et al, 2011). PIAS1 and MYC weakly co-IP in resting B-cells but readily co-IP in LPS and LPS/IL4 treated B-cells.…”

Section: Resultsmentioning

confidence: 92%

“…Nevertheless, the SAE1/2 SUMO E1 ligase is essential for the viability of MYC-dependent breast cancer cell lines (Kessler et al, 2012). Targeting the SUMOylation machinery leads to detrimental effects also in B-cell lymphoma cells (Hoellein et al, 2014). These observations suggest that components of the cellular machinery that SUMOylates MYC represents a potential therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

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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: 92%

Section: Introductionmentioning

confidence: 99%

PIAS1 Promotes Lymphomagenesis through MYC Upregulation

et al. 2016

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“…Several compounds that target SAE1/SAE2 or UBC9 are entering clinical testing. We also reason that PIAS1 could be a worthy therapeutic target (45,49). We expect that future studies combining cancer genetics, functional studies and in vivo models will continue to increase our understanding of the role of the SUMOylation machinery in cancer and in determining the response to therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with this view, several components of the SUMOylation machinery are up-regulated by MYC in mouse and human B-cell lymphomas. Furthermore, inhibition of SUMOylation induces the apoptosis of MYC-dependent lymphoma cells (45). …”

Section: Pias1 Myc and Lymphomagenesismentioning

confidence: 99%

The Role of PIAS SUMO E3-Ligases in Cancer

2017

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SUMOylation modifies the interactome, localization, activity and lifespan of its target proteins. This process regulates several cellular machineries, including transcription, DNA damage repair, cell-cycle progression and apoptosis. Accordingly, SUMOylation is critical in maintaining cellular homeostasis and its deregulation leads to the corruption of a plethora of cellular processes that contribute to disease states. Among the proteins involved in SUMOylation, the Protein Inhibitor of Activated STAT (PIAS) E3-ligases were initially described as transcriptional co-regulators. Recent findings also indicate that they have a role in regulating protein stability and signaling transduction pathways. PIAS proteins interact with up to 60 cellular partners affecting several cellular processes, most notably immune regulation and DNA repair, but also cellular proliferation and survival. Here we summarize the current knowledge about their role in tumorigenesis and cancer-related processes.

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“…This over expression of Myc genes is thought to be responsible for cancer through disruptions in ubiquitin-protesome system (Hoellein et al, 2014). It is argued and consequently proven by Hoellein et al, (2014) that SUMOylation plays critical roles in Myc dependent tumorigenesis showing over expression of genes involved in SUMOylation pathway both in humans and mouse lymphoma causing increased SUMOylation in these tumors while inhibiting SUMOylation through genetic means causes inhibition of Myc driven proliferation, stimulating G2/M phase cell cycle arrest, apoptosis and polyploidy (Hoellein et al, 2014). Furthermore, a rapid regression is observed in Myc lymphoma by inhibiting S U M O y l a t i o n i n -v i v o b o t h g e n e t i c a l l y a n d pharmacologically (Hoellein et al, 2014) hence providing yet another SUMOylation related therapeutic target that can be used in Myc driven lymphomas.…”

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confidence: 99%

SUMOylation: A link to future therapeutics

2016

Current Issues in Molecular Biology

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SUMOylation, much of a similar process like ubiquitination catches attention across various research groups as a potential therapeutic target to fight various infectious and cancerous diseases. This idea take its strength from recent reports which unearth the molecular mechanisms of SUMOylation and its involvement in important diseases distributed across various kingdoms. At the beginning SUMOylation was considered a process affected only by viral diseases but subsequent reports enlighten its role in diseases caused by bacteria as well. This enhances the SUMOylation canvas and demanded more in-depth study of the process. The present review is an attempt to study the regulatory mechanism of genes when the natural SUMOylation pathway is disturbed, the cross-talk among SUMOylation and other post translational modifications, the role of miRNAs in controlling the function of transcripts, loading of RNA species into exosomes and the possible SUMOylation related therapeutic targets. IntroductionThe innate immune responses across kingdoms are tightly regulated to fight attacking pathogens. Post translational modification of proteins like acetylation, methylation, ubiquitination and SUMOylation have predominant role in activation/deactivation of immune responses by regulating various cellular processes including transcription, DNA repair, proliferation and apoptosis as these have the potential to relocate the protein to different organelles and modify its biological function. The deep understanding of those post translational mechanisms could provide insights in controlling several disease conditions and develop therapeutics based on those post translational modification markers.The small ubiquitin like modifiers (SUMO) proteins discovered in 1997 (Mahajan et al., 1997) has since been recognized as family of important modification proteins unlike ubiquitination which is involved in degradation of proteins, instead it modulates the function of target proteins. The covalent conjugation of SUMO molecules to protein residue lysine on a typical consensus sequence ψKxD/E (where ψ is large hydrophobic residue, K is the target lysine, D/E is acidic residue and x represent any amino acid) (Rodriguez et al., 2001;Sampson et al., 2001). The process of SUMOylation is carried out by a cascade of three enzymes (E1, E2 and E3). E1 is a SUMO activating enzyme SAE1, while E2 is conjugating enzyme e.g. Ubc9 and E3 is SUMO ligase. The SUMOylation reaction is reversed by SENPs termed as deSUMOylation having distinct regulatory roles. Till date four SUMO molecules have been reported in mammals viz., SUMO1, SUMO2, SUMO3 and SUMO4. The sequence similarity of SUMO2 and SUMO3 are almost 97% hence are often reported collectively as SUMO2/3. Various kinds of stimuli like oxidative stress often increase the rate of SUMOylation. A recent report shows the exposure to cigarette smoke alters the microRNA expression by SUMOylation of DICER (Gross et al., 2014). Viruses and chemical toxins also causes an increase in SUMOylation, a well known exam...

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Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma

Abstract: Key Points The Myc oncoprotein targets central regulators of the SUMOylation machinery, resulting in a hyper-SUMOylation state in Myc-induced lymphoma. Targeting SUMOylation by genetic or pharmacologic means represents a novel therapeutic option for lymphomas with MYC involvement.

Cited by 79 publications

References 58 publications

PIAS1 Promotes Lymphomagenesis through MYC Upregulation

PIAS1 Promotes Lymphomagenesis through MYC Upregulation

The Role of PIAS SUMO E3-Ligases in Cancer

SUMOylation: A link to future therapeutics

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