Pc2‐mediated SUMOylation of WWOX is essential for its suppression of DU145 prostate tumorigenesis

Choi, Hye‐Jin; Park, Jung Hwan; Park, Jong‐Hwan; Lee, Kyung Bok; Oh, Sang‐Muk

doi:10.1016/j.febslet.2015.11.028

Cited by 6 publications

(6 citation statements)

References 45 publications

(59 reference statements)

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“…In addition, vesicle trafficking protein TRAPPC6A binds WWOX and acts as a carrier for WWOX to undergo nuclear accumulation (Chang and Chang, 2015). Interestingly, WWOX can be subjected to E3 ligase polycomb2 (Pc2)-mediated SUMOylation, and this enables its suppression of DU145 prostate cancer tumorigenesis (Choi et al, 2015). Activated tyrosine kinase Cdc42-associated kinase (ACK1) promotes prostate cancer progression, via binding and phosphorylating WWOX at Tyr287 for polyubiquitination and proteosomal degradation (Mahajan et al, 2005).…”

Section: Tumor Suppressor Wwox Is Anchored On the Cell Membrane By Hymentioning

confidence: 99%

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Hsu

Chiang

Sze

et al. 2016

Front. Cell Dev. Biol.

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Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3− CD19− Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.

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Section: Tumor Suppressor Wwox Is Anchored On the Cell Membrane By Hymentioning

confidence: 99%

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Hsu

Chiang

Sze

et al. 2016

Front. Cell Dev. Biol.

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“…WWOX can undergo modification by small ubiquitin-like modifier (SUMO) proteins. As a result, the SUMOylated WWOX blocks prostate cancer growth [ 80 ].…”

Section: Dramatic Upregulation Of Py33- and Py287-wwox In The Brain C...mentioning

confidence: 99%

Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration

Chen,

Liu,

Wen

et al. 2024

IJMS

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We reported that a 31-amino-acid Zfra protein (zinc finger-like protein that regulates apoptosis) blocks neurodegeneration and cancer growth. Zfra binds WW domain-containing oxidoreductase (WWOX) to both N- and C-termini, which leads to accelerated WWOX degradation. WWOX limits the progression of neurodegeneration such as Alzheimer’s disease (AD) by binding tau and tau-hyperphosphorylating enzymes. Similarly, Zfra binds many protein targets and accelerates their degradation independently of ubiquitination. Furthermore, Zfra4-10 peptide strongly prevents the progression of AD-like symptoms in triple-transgenic (3xTg) mice during aging. Zfra4-10 peptide restores memory loss in 9-month-old 3xTg mice by blocking the aggregation of a protein cascade, including TPC6AΔ, TIAF1, and SH3GLB2, by causing aggregation of tau and amyloid β. Zfra4-10 also suppresses inflammatory NF-κB activation. Zfra-activated Hyal-2+ CD3- CD19- Z cells in the spleen, via Hyal-2/WWOX/Smad4 signaling, are potent in cancer suppression. In this perspective review, we provide mechanistic insights regarding how Zfra overrides WWOX to induce cancer suppression and retard AD progression via Z cells.

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“…The tumor suppressor WW domain-containing oxidoreductase (WWOX) is downregulated in many tumors, such as breast, ovarian, GC, HCC and lung cancers [ 281 , 282 , 283 , 284 , 285 ]. The sumoylation of WWOX mediated by CBX4 promotes its suppressive activity on the oncogene JUN , and in the PCa cell line DU145, it has been demonstrated that decreases cell proliferation, indicating that this PTM is essential for its tumor suppressor activity [ 211 ]. However, negative functions have also been observed in relation to this SUMO E3 ligase, showing a recent study that CBX4 promotes cell growth and metastasis in PCa [ 212 ].…”

Section: Sumo Ligases In Cancermentioning

confidence: 99%

Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases

Lara-Ureña

Jafari

García‐Domínguez

2022

IJMS

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SUMOylation is a post-translational modification that has emerged in recent decades as a mechanism involved in controlling diverse physiological processes and that is essential in vertebrates. The SUMO pathway is regulated by several enzymes, proteases and ligases being the main actors involved in the control of sumoylation of specific targets. Dysregulation of the expression, localization and function of these enzymes produces physiological changes that can lead to the appearance of different types of cancer, depending on the enzymes and target proteins involved. Among the most studied proteases and ligases, those of the SENP and PIAS families stand out, respectively. While the proteases involved in this pathway have specific SUMO activity, the ligases may have additional functions unrelated to sumoylation, which makes it more difficult to study their SUMO-associated role in cancer process. In this review we update the knowledge and advances in relation to the impact of dysregulation of SUMO proteases and ligases in cancer initiation and progression.

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Pc2‐mediated SUMOylation of WWOX is essential for its suppression of DU145 prostate tumorigenesis

Cited by 6 publications

References 45 publications

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration

Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases

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