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2. Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression

Author

Liu, Juan, Zhang, Cen, Wu, Hao, Sun, Xiao-Xin, Li, Yanchen, Huang, Shan, Yue, Xuetian, Lu, Shou-En, Shen, Zhiyuan, Su, Xiaoyang, White, Eileen, Haffty, Bruce G., Hu, Wenwei, and Feng, Zhaohui

Subjects
The Jackson Laboratory, International economic relations, Development and progression, Lung cancer -- Development and progression, Ubiquitin, Cancer -- Development and progression, Ligases, Serine
Abstract

Introduction Cancer cells reprogram their metabolism to meet their bioenergetic and biosynthetic needs for rapid growth and proliferation (1-3). Increased serine biosynthesis is an important metabolic adaptation in many human [...], Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson's disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.

Published
2020
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6. Deregulating MYC in a model of [HER2.sup.+] breast cancer mimics human intertumoral heterogeneity

Author

Risom, Tyler, Wang, Xiaoyan, Liang, Juan, Zhang, Xiaoli, Pelz, Carl, Campbell, Lydia G., Eng, Jenny, Chin, Koei, Farrington, Caroline, Narla, Goutham, Langer, Ellen M., Sun, Xiao-Xin, Su, Yulong, Daniel, Colin J., Dai, Mu-Shui, Lohr, Christiane V., and Sears, Rosalie C.

Subjects
Health aspects, Pertuzumab -- Health aspects, Lapatinib -- Health aspects, Breast cancer -- Health aspects, Neratinib -- Health aspects, Estrogens, Therapeutics, Phenols (Class of compounds), Phosphatases, Cancer metastasis, Tumors, Phenotypes, Diseases
Abstract

Introduction Amplified-HER2 breast cancer is an aggressive disease that until recently had the worst overall survival prognosis among breast cancer subtypes (1, 2). The clinical implementation of HER2-targeted therapies, including [...], The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in [HER2.sup.+] disease, examining the relationship between HER2 expression and MYC phosphorylation in [HER2.sup.+] patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC; NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC; NeuNT tumors match existing subtypes of amplified-HER2, estrogen receptor-negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR-targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers.

Published
2020
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9. The ubiquitin-specific protease USP36 SUMOylates EXOSC10 and promotes the nucleolar RNA exosome function in rRNA processing

Author

Chen, Yingxiao, primary, Li, Yanping, additional, Dai, Roselyn S, additional, Savage, Jonathan C, additional, Shinde, Ujwal, additional, Klimek, John, additional, David, Larry L, additional, Young, Emma A, additional, Hafner, Markus, additional, Sears, Rosalie C, additional, Sun, Xiao-Xin, additional, and Dai, Mu-Shui, additional

Published
2023
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28. Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity

Author

Risom, Tyler, primary, Wang, Xiaoyan, additional, Liang, Juan, additional, Zhang, Xiaoli, additional, Pelz, Carl, additional, Campbell, Lydia G., additional, Eng, Jenny, additional, Chin, Koei, additional, Farrington, Caroline, additional, Narla, Goutham, additional, Langer, Ellen M., additional, Sun, Xiao-Xin, additional, Su, Yulong, additional, Daniel, Colin J., additional, Dai, Mu-Shui, additional, Löhr, Christiane V., additional, and Sears, Rosalie C., additional

Published
2019
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32. p73 to the rescue: Role of RPL26

Author

Sun, Xiao-Xin and Dai, Mu-Shui

Subjects
p53, ribosomal stress, p73, ribosome biogenesis, News, RPL26
Published
2016

33. Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1

Author

Sun, Xiao-Xin and Dai, Mu-Shui

Subjects
Review
Abstract

Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes (DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. We recently reported that Otub1, a DUB from the OTU-domain containing protease family, is a novel p53 regulator. Interestingly, Otub1 abrogates p53 ubiquitination and stabilizes and activates p53 in cells independently of its deubiquitinating enzyme activity. Instead, it does so by inhibiting the MDM2 cognate ubiquitin-conjugating enzyme (E2) UbcH5. Otub1 also regulates other biological signaling through this non-canonical mechanism, suppression of E2, including the inhibition of DNA-damage-induced chromatin ubiquitination. Thus, Otub1 evolves as a unique DUB that mainly suppresses E2 to regulate substrates. Here we review the current progress made towards the understanding of the complex regulation of the p53 tumor suppressor pathway by DUBs, the biological function of Otub1 including its positive regulation of p53, and the mechanistic insights into how Otub1 suppresses E2.

Published
2014

35. Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1

Author

Sun, Xiao-Xin, Challagundla, Kishore B, and Dai, Mu-Shui

Subjects
Base Sequence, Deubiquitinating Enzymes, Transcription, Genetic, Proto-Oncogene Proteins c-mdm2, Article, enzymes and coenzymes (carbohydrates), Cysteine Endopeptidases, Cell Line, Tumor, Gene Knockdown Techniques, Biocatalysis, Humans, Tumor Suppressor Protein p53, neoplasms, Cell Proliferation, DNA Damage, DNA Primers, Protein Binding
Abstract

The ubiquitin (Ub)-proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. p53 is ubiquitinated and destabilized by MDM2 and several other Ub E3s, whereas it is deubiquitinated and stabilized by Ub-specific protease (USP)7 and USP10. Here we show that the ovarian tumour domain-containing Ub aldehyde-binding protein 1 (Otub1) is a novel p53 regulator. Otub1 directly suppresses MDM2-mediated p53 ubiquitination in cells and in vitro. Overexpression of Otub1 drastically stabilizes and activates p53, leading to apoptosis and marked inhibition of cell proliferation in a p53-dependent manner. These effects are independent of its catalytic activity but require residue Asp88. Mutation of Asp88 to Ala (Otub1(D88A)) abolishes activity of Otub1 to suppress p53 ubiquitination. Further, wild-type Otub1 and its catalytic mutant (Otub1(C91S)), but not Otub1(D88A), bind to the MDM2 cognate E2, UbcH5, and suppress its Ub-conjugating activity in vitro. Overexpression of Otub1(D88A) or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity.

Published
2011

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