Low PIAS3 Expression in Malignant Mesothelioma Is Associated with Increased STAT3 Activation and Poor Patient Survival

Dabir, Snehal; Kluge, Amy; Kresak, Adam; Yang, Michael; Fu, Pingfu; Groner, Bernd; Wildey, Gary; Dowlati, Afshin

doi:10.1158/1078-0432.ccr-14-1233

Cited by 40 publications

(42 citation statements)

References 43 publications

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“…Recent evidence indicates that PIAS3 has been associated with tumor cell migration and survival in glioblastoma multiforme and prostate cancer (34,35), and abnormal expression of PIAS3 in tumors is associated with malignant properties of tumor cells (36)(37)(38). The role of PIAS3 in tumor cells indicates the relation between PIAS3 and the aggressive nature of RA FLSs.…”

Section: Discussionmentioning

confidence: 99%

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Lao

Shi

Zou

et al. 2016

The Journal of Immunology

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The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) is a critical factor of cartilage destruction in rheumatoid arthritis (RA). Increased FLSs migration and subsequent degradation of the extracellular matrix are essential to the pathology of RA. Protein inhibitor of activated STAT (PIAS), whose family members include PIAS1, PIAS2 (PIASx), PIAS3, and PIAS4 (PIASy), play important roles in regulating various cellular events, such as cell survival, migration, and signal transduction in many cell types. However, whether PIAS proteins have a role in the pathogenesis of RA is unclear. In this study, we evaluated the role of PIAS proteins in FLSs migration, invasion, and matrix metalloproteinases (MMPs) expression in RA. We observed increased expression of PIAS3, but not PIAS1, PIAS2, or PIAS4, in FLSs and synovial tissues from patients with RA. We found that PIAS3 knockdown by short hairpin RNA reduced migration, invasion, and MMP-3, MMP-9, and MMP-13 expression in FLSs. In addition, we demonstrated that PIAS3 regulated lamellipodium formation during cell migration. To gain insight into molecular mechanisms, we evaluated the effect of PIAS3 knockdown on Rac1/PAK1 and JNK activation. Our results indicated that PIAS3-mediated SUMOylation of Rac1 controlled its activation and modulated the Rac1 downstream activity of PAK1 and JNK. Furthermore, inhibition of Rac1, PAK1, or JNK decreased migration and invasion of RA FLSs. Thus, our observations suggest that PIAS3 suppression may be protective against joint destruction in RA by regulating synoviocyte migration, invasion, and activation.

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Section: Discussionmentioning

confidence: 99%

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Lao

Shi

Zou

et al. 2016

The Journal of Immunology

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“…The role of PIAS3 as a modulator of ATR may explain its implication in HR (19). PIAS3 expression is low in significant fractions of squamous cell lung cancer (SCC), non-small cell lung cancer (NSCLC), gastric cancer (GC), and mesothelioma (37)(38)(39)(40). The low expression of PIAS3 correlates with STAT3/5 activation and poor patient survival.…”

Section: Discussionmentioning

confidence: 99%

The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation

Zou

2016

Journal of Biological Chemistry

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The maintenance of genomic stability relies on the concerted action of DNA repair and DNA damage signaling pathways. The PIAS (protein inhibitor of activated STAT) family of SUMO (small ubiquitin-like modifier) ligases has been implicated in DNA repair, but whether it plays a role in DNA damage signaling is still unclear. Here, we show that the PIAS3 SUMO ligase is important for activation of the ATR (ataxia telangiectasia and Rad3 related)-regulated DNA damage signaling pathway. PIAS3 is the only member of the PIAS family that is indispensable for ATR activation. In response to different types of DNA damage and replication stress, PIAS3 plays multiple roles in ATR activation. In cells treated with camptothecin (CPT), PIAS3 contributes to formation of DNA double-stranded breaks. In UV (ultraviolet light)-or HU (hydroxyurea)-treated cells, PIAS3 is required for efficient ATR autophosphorylation, one of the earliest events during ATR activation. Although PIAS3 is dispensable for ATRIP (ATR-interacting protein) SUMOylation and the ATR-ATRIP interaction, it is required for maintaining the basal kinase activity of ATR prior to DNA damage. In the absence of PIAS3, ATR fails to display normal kinase activity after DNA damage, which accompanies with reduced phosphorylation of ATR substrates. Together, these results suggest that PIAS3 primes ATR for checkpoint activation by sustaining its basal kinase activity, revealing a new function of the PIAS family in DNA damage signaling.Multiple types of post-translational modifications (PTMs), 2 including protein SUMOylation, are important for regulation of the DNA damage response (DDR) from yeast to human (1, 2). Several SUMO E3 ligases, particularly the members of the PIAS family, are shown to modify DDR proteins. In the budding yeast, the PIAS family member Siz1 SUMOylates PCNA during S phase, promoting the recruitment of Srs2 to replication forks to suppress unwanted recombination (3-6). Siz2, the second PIAS ligase in yeast, SUMOylates a large number of DNA replication and repair proteins in response to DNA damage, which may enhance the efficiency of DNA repair by stabilizing multiple protein interactions in repair complexes (7,8). A recent study showed that Siz2 is recruited to sites of DNA damage through its interaction with RPA, a sensor of single-stranded DNA (ssDNA), explaining the regulation of protein SUMOylation by DNA damage (9). Together these findings in yeast clearly show that the PIAS family SUMO ligases are critical regulators of the DDR.In human cells, four members of the PIAS family SUMO ligases have been identified: PIAS1, PIAS2 (PIASx␣/␤), PIAS3, and PIAS4 (PIASy) (10). Two of these SUMO ligases, PIAS1 and PIAS4, are recruited to sites of DNA damage (11). Both PIAS1 and PIAS4 contribute to the efficient recruitment of 53BP1, BRCA1, and RNF168 (11). A number of DDR proteins, such as 53BP1, BRCA1, MDC1, HERC2, RNF168, FNACI, and FANCD2, are SUMOylated by PIAS1 and/or PIAS4. The SUMOylation of these DDR proteins regulate their functions in several different w...

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“…Previously, we have shown that PIAS3 is a tumor suppressor in MM cells and that low PIAS3 protein expression predicted poor survival in MM patients (Dabir et al ., ). Because our results here support a role for miR‐18a in the regulation of PIAS3 protein expression in MM cell lines, we investigated its potential role as a therapeutic target in MM cells by inhibiting miR‐18a in cells and by determining its clinical importance in MM patient survival using the TCGA database (https://cancergenome.nih.gov/).…”

Section: Resultsmentioning

confidence: 97%

Post‐transcriptional regulation of PIAS3 expression by miR‐18a in malignant mesothelioma

et al. 2018

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Protein inhibitor of activated STAT3 (PIAS3) is an endogenous suppressor of signal transducer and activator of transcription 3 (STAT3) signaling. By directly interacting with phosphorylated STAT3, PIAS3 can block the downstream transcriptional activity of STAT3, which is hyper‐activated in various cancers. We previously reported that in malignant mesothelioma (MM), low PIAS3 expression is associated with increased STAT3 activation and correlates with poor patient survival, yet the regulatory mechanism(s) governing PIAS3 expression in MM remain unclear. Here, we demonstrate that PIAS3 protein expression does not correlate with its mRNA level in MM cell lines, indicating that PIAS3 expression is regulated at a post‐transcriptional level. Inhibition of proteasomal degradation with MG132 (10 μm) or bortezomib (1 μm), alone and in combination, did not increase PIAS3 protein levels; furthermore, inhibition of protein synthesis by cycloheximide treatment did not decrease PIAS3 levels within 48 h, suggesting that PIAS3 expression is not actively regulated at a post‐translational level. To determine whether miRNA (miRs) can translationally regulate PIAS3 expression, we combined miR microarray analysis with bioinformatic screening to identify candidate miRs, in MM cell lines with low PIAS3 expression, followed by luciferase reporter assays to validate miR regulation of the PIAS3 3′UTR. We identified miR‐18a as a suppressor of PIAS3 expression that is upregulated in MM cells and whose inhibition can increase PIAS3 expression and suppress STAT3 activity. Moreover, we showed that miR‐18a inhibition can decrease MM cell viability and that its expression is negatively correlated with MM patient survival. Taken together, these results suggest that targeting miR‐18a may have therapeutic benefit in MM.

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Low PIAS3 Expression in Malignant Mesothelioma Is Associated with Increased STAT3 Activation and Poor Patient Survival

Cited by 40 publications

References 43 publications

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation

Post‐transcriptional regulation of PIAS3 expression by miR‐18a in malignant mesothelioma

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