Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation

Wu, Fei; Dai, Xiangpeng; Gan, Wenjian; Wan, Lixin; Li, Min; Mitsiades, Nicholas; Wei, Wenyi; Ding, Qiang; Zhang, Jinfang

doi:10.1016/j.canlet.2016.10.021

Cited by 39 publications

(33 citation statements)

References 48 publications

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“…Recently, Sackton et al (26) reported that apcin directly disturbed the binding of Cdc20 to its substrates and subsequently blocked mitotic exit in human cancer cells. Apcin inhibited the oncogenic function of Cdc20 by reducing cell viability and inducing apoptosis in a dose-dependent manner in prostate cancer cells (39). Furthermore, it was reported that Speckle-type POZ protein (SPOP)-deficient prostate cancer cells were resistant to apcin, suggesting that apcin could be clinically used to treat patients with SPOP-WT prostate cancer, but not SPOP-deficient prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells

et al. 2018

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Osteosarcoma (OS) is the most common primary malignant bone tumor worldwide, primarily affecting children and adolescents. The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that is activated by its co‑activator Cdc20 during the metaphase‑anaphase transition. Apcin is a novel cell‑permeable molecule that blocks the interaction between APC/C and Cdc20. Cdc20 overexpression has been reported in various malignancies and plays an oncogenic role in tumorigenesis and tumor progression. In the present study, the antitumor properties of apcin, an inhibitor of Cdc20, was investigated in OS cell lines. In addition, the possible molecular target by which apcin mediates cell death was explored. Apcin was demonstrated to inhibit OS cell growth and induce significant apoptosis. The invasion and mobile abilities of OS cells were also markedly suppressed by apcin treatment. Furthermore, Bim and p21 were upregulated in OS cells following apcin treatment. The results of the present study indicated that apcin may have therapeutic potential as a treatment for OS and that Cdc20 may be a promising molecular target for chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells

et al. 2018

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“…The CRL3 E3 ligase containing SPOP acts as a tumor suppressor by promoting the degradation of several oncogenes, including ERG and CDC20 (296), an activator of the APC/C E3 ligase. Consequently, mutations that inactivate SPOP function are present in 15% of prostate cancers (193).…”

Section: Tumorigenesis: Somewhere Between Neutrality and Lethalitymentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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“…SPOP suppresses tumorigenesis and progression via regulation of cell growth, apoptosis, migration, invasion and drug resistance by targeting its downstream substrates in several types of human malignancies, including prostate, lung, gastric, liver, colon and endometrial cancers SPOP mutations and downregulation were detected in human PrCa tissues, and these mutations were also tightly correlated with a worse prognosis in patients with PrCa [61]. More importantly, extensive biochemical evidence has further indicated that SPOP functions as a tumor suppressor by promoting the degradation of oncogenic substrates in PrCa, including SRC3 [62], AR [63], TRIM24 [64], c-Myc [65], DEK [66], SENP7 [67], EglN2 [68], ATF2 [69], Cdc20 [70], ERG [71,81], BRD4 [72][73][74], PD-L1 [75] and cyclin E1 [76]. Due to the many publications and space limitations, we will not describe the tumor suppressive role that SPOP plays by promoting the ubiquitination and degradation of its substrates in PrCa in detail.…”

Section: Prostate Cancer (Prca)mentioning

confidence: 99%

The emerging role of SPOP protein in tumorigenesis and cancer therapy

Song

Pan

et al. 2020

Mol Cancer

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The nuclear speckle-type pox virus and zinc finger (POZ) protein (SPOP), a representative substrate-recognition subunit of the cullin-RING E3 ligase, has been characterized to play a dual role in tumorigenesis and cancer progression. Numerous studies have determined that SPOP suppresses tumorigenesis in a variety of human malignancies such as prostate, lung, colon, gastric, and liver cancers. However, several studies revealed that SPOP exhibited oncogenic function in kidney cancer, suggesting that SPOP could exert its biological function in a cancer type-specific manner. The role of SPOP in thyroid, cervical, ovarian, bone and neurologic cancers has yet to be determined. In this review article, we describe the structure and regulation of SPOP in human cancer. Moreover, we highlight the critical role of SPOP in tumorigenesis based on three major categories: physiological evidence (animal models), pathological evidence (human cancer specimens) and biochemical evidence (downstream ubiquitin substrates). Furthermore, we note that SPOP could be a promising therapeutic target for cancer treatment.

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Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation

Cited by 39 publications

References 48 publications

Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells

Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells

Degrons in cancer

The emerging role of SPOP protein in tumorigenesis and cancer therapy

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