Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation

Andrio, Emilie; Lotte, Romain; Hamaoui, Daniel; Cherfils, Jacqueline; Doye, Anne; Daugaard, Mads; Sorensen, Poul H.; Bost, Fréd́eric; Ruimy, Raymond; Mettouchi, Amel; Lemichez, Emmanuel

doi:10.1038/srep44779

Cited by 23 publications

(27 citation statements)

References 26 publications

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“…Moreover, HACE1 down-regulation cooperates with ErbB2/HER2 overexpression in mammary cells to induce Rac1 hyperactivation, migration, malignant transformation, and tumorigenesis in vivo , effects that are sensitive to pharmacological Rac inhibition (27). A very recent report that identified cancer-associated missense mutations in HACE1 leading to defective Rac1 ubiquitination highlights the relevance of the control of Rac1 expression in cancer cell proliferation (28). …”

Section: Emerging Paradigms In Rho Gtpase Hyperactivation In Cancermentioning

confidence: 99%

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

2017

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Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase activating proteins (GAPs) also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anti-cancer agents, including targeted therapies, as well as to the suppression of anti-tumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting.

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Section: Emerging Paradigms In Rho Gtpase Hyperactivation In Cancermentioning

confidence: 99%

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

2017

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“…HECT domain and ankyrin repeat‐containing E3 ubiquitin protein Ligase (HACE1), one member of the HECT domain‐containing E3 ligase family, was first brought into our attention by the study of Wilms’ tumor and was then frequently found lost or down‐regulated in many kinds of tumors , suggesting its role as a tumor suppressor. However, its special and pivotal role in tumor suppression was merely understood except for some discoveries suggesting that HACE1 could restrain reactive oxygen species generation , control cell fate through regulating TNFR1 , and impede cell growth by accelerating ubiquitylation of Rac1 . In previous work, we uncovered a special function of HACE1 as suppressing tumors by enhancing selective autophagy .…”

Section: Introductionmentioning

confidence: 99%

Overexpression of HACE1 in gastric cancer inhibits tumor aggressiveness by impeding cell proliferation and migration

Chen

Jiang

et al. 2018

Cancer Medicine

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HACE1 E3 ligase was discovered to be down‐regulated in several cancers while its role in regulating tumors was merely understood. This study aimed to explore the specific effect of HACE1 played in gastric tumorigenesis and its potential mechanism. HACE1's expression was found significantly lower in gastric cancer tissues compared with the adjacent normal tissues (P < 0.001). Its protein level in gastric cancer negatively correlated to tumor pathological differentiation (P = 0.019). And in gastric cancer patients with TNM I‐IIIa, those with lower HACE1 protein level had poorer overall survival (P = 0.025). Studies, in vivo and in vitro, showed that overexpressing HACE1 inhibited tumor proliferation and migration, and enhanced cell apoptosis. Besides, ectopic expression of HACE1 down‐regulated the protein level of β‐catenin and inhibited the activity of the Wnt/β‐catenin signaling pathway. All the cellular functions were abolished when we overexpressed inactive HACE1‐deltaHECT. Above all, we demonstrated that HACE1 E3 ligase played a suppressive role in gastric tumorigenesis and inhibited the activity of the Wnt/β‐catenin signaling pathway. Circumventing the decline of HACE1 in early stage of carcinoma may impede the tumorigenesis and malignant process of gastric cancer.

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“…proteins [57,58,[61][62][63][64][65]. Expanded studies on how HACE1 binds and recognizes its substrates are needed to further clarify the role of HACE1 in cancer development.…”

Section: Hace1 a Prominent Tumor Suppressor With Dual Functionmentioning

confidence: 99%

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Kane¹,

Spratt²

2020

Ubiquitin - Proteasome Pathway

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HECT E3 ubiquitin ligases selectively recognize, bind, and ubiquitylate their substrate proteins to target them for 26S proteasomal degradation. There is increasing evidence that HECT E3 ubiquitin ligase dysfunction due to misfolding and/or the gene encoding the protein being mutated is responsible for the development of different diseases. Apart from the more prominent and well-characterized E6AP and members of the NEDD4 family, new studies have begun to reveal how other members of the HECT E3 ubiquitin ligase family function as well as their links to disease and developmental disorders. This chapter provides a comprehensive discussion on the more mysterious members of the HECT E3 ubiquitin ligase family and how they control intracellular processes. Specifically, AREL1, HACE1, HECTD1, HECTD4, G2E3, and TRIP12 will be examined as these enzymes have recently been identified as contributors to disease development.2 covalently attach ubiquitin on to a lysine residue of the substrate protein forming a stable isopeptide bond between the C-terminus of ubiquitin and the ε-amine of the substrate lysine [3,5,6]. This process can be repeated numerous times to form different polyubiquitin chain linkages with the specific HECT E3 ubiquitin ligase dictating the type(s) of ubiquitin linkages that are built [2,7]. Chain typesLinker Proposed function Monoubiquitylation Monoubiquitylation/ multi-monoubiquitylation Endocytosis [9] DNA damage repair [10-15] Histone regulation [10-15] Mitophagy [10-15] Protein localization [10-15] Protein interactions [10-15] Protein transportation [10-15] Transcription activation [10-15] Polyubiquitylation Chain (homotypic) M1 Innate immunity [2, 9, 16] Linear chain formation [9] NF-κB activation [9, 16] Signaling cascades [9, 16] K6 DNA damage response [14] NF-κB regulation [14] Mitophagy [14] K11 Cell cycle regulation [17] DNA damage response [18] Mitophagy [17] NF-κB activation [16] Protein degradation [17] K27 DNA damage response [18] Kinase activation [19] Protein degradation [20] Protein scaffolding [21] Protein trafficking [22] K29 DNA damage response [18] Kinase activation [19] Protein degradation [9] K33 DNA damage response [10-15, 18] Kinase activation [23] Post-golgi trafficking [24] T-cell signaling [23] K4 8 Protein degradation [1, 2, 25] K63 DNA damage response [9, 18] NF-κB activation [9, 16] Protein trafficking [9] Chain (heterotypic; branched) M1 /K63 NF-κB activation [16] K11 /K4 8 Protein degradation [26, 27] K29/K48 Protein degradation [26] K48/K63 Protein degradation [26] K11 /K63 Endocytosis [28]

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Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation

Cited by 23 publications

References 26 publications

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Overexpression of HACE1 in gastric cancer inhibits tumor aggressiveness by impeding cell proliferation and migration

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

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