The PIAS3-Smurf2 sumoylation pathway suppresses breast cancer organoid invasiveness

Chandhoke, Amrita Singh; Chanda, Ayan; Karve, Kunal; Deng, Lili; Bonni, Shirin

doi:10.18632/oncotarget.15471

Cited by 33 publications

(32 citation statements)

References 37 publications

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“…In addition to its regulation on STAT3, PIAS3 exhibits anti-tumorigenic roles via other mechanisms, including regulating nuclear factor-κB, PI3K/AKT, and TGFβ pathways 11 , 14 , 25 , 37 , reducing the activity of transcription factors such as MITF, Oct4, and others 38 , 39 . As a SUMO (small ubiquitin-like modifier)-E3 ligase, the anti-tumor functions of PIAS3 are also associated with sumoylation enhancement and degradation of oncoproteins 40 – 42 , as well as a promoting regulation of p53 and ATR by inducing p53 sumoylation 43 – 45 . The complicated mechanisms of PIAS3 in tumorigenesis indicate that besides STAT3, other potential downstream pathways mediating the cancer-promotion of Smad6–PIAS3 axis in gliomas still need to be studied.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition

Jiao

Zhang

et al. 2018

Nat Commun

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To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation.

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Section: Discussionmentioning

confidence: 99%

Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition

Jiao

Zhang

et al. 2018

Nat Commun

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“…GRIN1 or NMDAR1 (N-Methyl-D-Aspartate Receptor Subunit NR1) was shown to be expressed in breast cancer specimens, but not in normal breast and to be involved in tumor growth [ 31 ], being thus, a potential oncogene. SMURF2 (SMAD specific E3 ubiquitin protein ligase 2) is a tumor suppressor involved in the maintenance of genomic stability and suppression of breast cancer cells invasiveness [ 32 , 33 ]. PIK3AP1 (phosphoinositide-3-kinase adaptor protein 1), also known as BCAP , is involved in the phosphatidylinositol 3-kinase (PI3K) pathway and genome wide association studies suggest that the PIK3AP1 gene region might be involved in breast cancer predisposition [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Somatic mutations in early onset luminal breast cancer

et al. 2018

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Breast cancer arising in very young patients may be biologically distinct; however, these tumors have been less well studied. We characterized a group of very young patients (≤ 35 years) for BRCA germline mutation and for somatic mutations in luminal (HER2 negative) breast cancer. Thirteen of 79 unselected very young patients were BRCA1/2 germline mutation carriers. Of the non-BRCA tumors, eight with luminal subtype (HER2 negative) were submitted for whole exome sequencing and integrated with 29 luminal samples from the COSMIC database or previous literature for analysis. We identified C to T single nucleotide variants (SNVs) as the most common base-change. A median of six candidate driver genes was mutated by SNVs in each sample and the most frequently mutated genes were PIK3CA, GATA3, TP53 and MAP2K4. Potential cancer drivers affected in the present non-BRCA tumors include GRHL2, PIK3AP1, CACNA1E, SEMA6D, SMURF2, RSBN1 and MTHFD2. Sixteen out of 37 luminal tumors (43%) harbored SNVs in DNA repair genes, such as ATR, BAP1, ERCC6, FANCD2, FANCL, MLH1, MUTYH, PALB2, POLD1, POLE, RAD9A, RAD51 and TP53, and 54% presented pathogenic mutations (frameshift or nonsense) in at least one gene involved in gene transcription. The differential biology of luminal early-age onset breast cancer needs a deeper genomic investigation.

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“…In addition, a recent study showed that knock-down of Smurf2 increases the proportion of invasive MDA-MB-231 cell-derived organoids. This group also demonstrated that PIAS3-dependent sumoylation of Smurf2 is important in suppressing the invasive behavior of these cells ( 77 ).…”

Section: Regulatory Roles Of Smurfs In the Decisive Cellular Processementioning

confidence: 95%

Smurfs in Protein Homeostasis, Signaling, and Cancer

2018

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Protein ubiquitination is an evolutionary conserved highly-orchestrated enzymatic cascade essential for normal cellular functions and homeostasis maintenance. This pathway relies on a defined set of cellular enzymes, among them, substrate-specific E3 ubiquitin ligases (E3s). These ligases are the most critical players, as they define the spatiotemporal nature of ubiquitination and confer specificity to this cascade. Smurf1 and Smurf2 (Smurfs) are the C2-WW-HECT-domain E3 ubiquitin ligases, which recently emerged as important determinants of pivotal cellular processes. These processes include cell proliferation and differentiation, chromatin organization and dynamics, DNA damage response and genomic integrity maintenance, gene expression, cell stemness, migration, and invasion. All these processes are intimately connected and profoundly altered in cancer. Initially, Smurf proteins were identified as negative regulators of the bone morphogenetic protein (BMP) and the transforming growth factor beta (TGF-β) signaling pathways. However, recent studies have extended the scope of Smurfs' biological functions beyond the BMP/TGF-β signaling regulation. Here, we provide a critical literature overview and updates on the regulatory roles of Smurfs in molecular and cell biology, with an emphasis on cancer. We also highlight the studies demonstrating the impact of Smurf proteins on tumor cell sensitivity to anticancer therapies. Further in-depth analyses of Smurfs' biological functions and influences on molecular pathways could provide novel therapeutic targets and paradigms for cancer diagnosis and treatment.

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The PIAS3-Smurf2 sumoylation pathway suppresses breast cancer organoid invasiveness

Cited by 33 publications

References 37 publications

Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition

Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition

Somatic mutations in early onset luminal breast cancer

Smurfs in Protein Homeostasis, Signaling, and Cancer

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