HERC Ubiquitin Ligases in Cancer: Comparison
Please note this is a comparison between Version 1 by Jose Luis Rosa and Version 3 by Bruce Ren.

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type.

  • HECT
  • E3
  • oncogene
  • tumor suppressor
  • genome stability
  • p53
  • MAPK
  • RAF
  • ERK
  • p38

1. Introduction

  1. Introduction

Ubiquitin E3 ligases take part in protein ubiquitylation. These enzymes catalyze the last step of a cascade where ubiquitin is initially incorporated to a ubiquitin-activating enzyme (E1), which in turn is transferred to a ubiquitin-conjugating enzyme (E2), and finally, to a target protein through a process defined by a ubiquitin E3 ligase that interacts with the substrate protein (Figure 1). The ubiquitin-like proteins SUMO, NEDD8, and ISG15 are also covalently attached to the target protein via an E1/E2/E3 cascade. Specifically, the E3 ligases can be classified into three groups, of which one is homologous to the E6AP carboxyl terminus (HECT) protein. All HECT ligases have a catalytic domain in their carboxyl terminus that contains a conserved cysteine residue that is involved in forming a transiently thioester bond to ubiquitin before transferring it to the lysine residue of the substrate protein (Figure 1) [1]. HECT ligases containing one or more regulator of chromosome condensation 1 (RCC1)-like domains in their amino-terminal domain form a HERC subgroup [2]. HERC1 and HERC2 are the largest HECT ligases, having molecular weights exceeding 500 kDa, and constitute the large HERC protein subfamily [3]. By contrast, HERC3 to HERC6 have molecular weights around 100–120 kDa and constitute the small HERC protein subfamily. Despite the structural similarity between large and small HERC proteins (Figure 1), they are evolutionarily very distant. In fact, they are the result of convergence phenomena rather than being phylogenetic paralogs [3][4][5][3–5]. Moreover, the small HERC proteins HERC5 and HERC6 may also function as ISG15 E3 ligases [6][7][6,7].

Figure 1. The ubiquitin-conjugating system in HERC E3 ligases: (A) Ubiquitin (Ub) is conjugated to a target substrate via a cascade that comprises an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase enzyme. The HERC proteins belong to the HECT family of E3 ligases, which form a thioester bond with Ub via a conserved cysteine residue. Once formed, Ub is transferred to the substrate’s lysine residue (see text for details). Ub-like proteins, such as ISG15, are also covalently attached to the substrate protein via an E1/E2/E3 cascade; (B) structural features of large and small HERC proteins are also shown. HERC5 and HERC6 may also function as ISG15 E3 ligases.

2. The Role of HERCs in Cancer

  1. The Role of HERCs in Cancer

HERCs play roles in a wide range of cellular functions, including neurodevelopment, cell response to replication stress and DNA damage, cell proliferation, cell migration, and immune responses. As such, mutations in HERCs are associated with severe pathologies [8][3,6,8], with a notable impact in cancer. An extensive list of the different cancers associated with the specific large and small HERCs is provided in Table 1.

 Table 1. Cancers associated with HERCs and related molecular mechanisms.

Genes

Associated Cancers

Related Molecular Mechanisms

Reference

HERC1

Acute promyelocytic leukemia

HERC1-PML genomic fusion

[9]

Acute Myeloid Leukemia

HERC1 mutations

[10]

Acute lymphoblastic leukemia

Decreased MSH2 protein levels and HERC1 deletions

[11]

Adult T-cell acute lymphoblastic leukemia

HERC1 mutations

[12]

T-cell prolymphocytic leukemia

HERC1 mutations

[13]

Non-melanoma skin cancer

Enhanced BAK protein degradation

[14]

Pulmonary sclerosing pneumocytoma

HERC1 mutations

[15]

Invasive lobular breast cancer

HERC1 mutations

[16]

Metastatic triple-negative breast cancer

HERC1 mutations

[17]

Sporadic colorectal cancer

Decreased MSH2 protein levels and HERC1 deletions

[11]

Osteosarcoma

Negative correlation of SOX18 overexpression and HERC1 mRNA levels

[18]

HERC2

Pheochromocytoma and paraganglioma

HERC2 mutations

[19]

T-cell prolymphocytic leukemia

HERC2 mutations

[13]

Cutaneous melanoma

SNPs in HERC2 gene increase susceptibility

[20][21][22][23][20–23]

Gene-gene interactions between HERC2 gene and IL31RA and DDX4 genes

[24]

Epistatic effects between HERC2 and VDR genes

[25]

Cutaneous squamous cell carcinoma

SNPs in HERC2 gene impact on time to develop the tumor in organ transplant recipients

[26]

Uveal melanoma

SNPs in HERC2 gene increase susceptibility

[27]

Non-small-cell lung cancer

Worse prognosis in patients expressing high HERC2 mRNA levels

[28]

Breast cancer

Enhanced BRCA1 degradation

[29][30][29,30]

Gastric and colorectal carcinomas

HERC2 mutations

[31]

Osteosarcoma

Negative correlation of SOX18 overexpression and HERC2 mRNA levels

[18]

HERC3

Glioblastoma

Degradation of SMAD7 and activation of the TGFβ signaling

[32]

Gastric and colorectal carcinomas

HERC3 mutations

[31]

Osteosarcoma

Negative correlation of SOX18 overexpression and HERC3 mRNA levels

[18]

HERC4

Multiple myeloma

Decreased c-Maf degradation

[33]

Lung cancer

HERC4 overexpression

[34]

Non-small cell lung cancer

Increased Smo protein stability and Hh pathway activation

[35][36][35,36]

Breast cancer

HERC4 upregulation

[37]

Decreased expression of miRNAs targeting HERC4 expression and enhanced LATS1 degradation

[38]

Hepatocellular carcinoma

HERC4 overexpression

[39]

Osteosarcoma

Negative correlation of SOX18 overexpression and HERC4 mRNA levels

[18]

HERC5

Pediatric germ cell tumors

Chromosome copy number variations (CNVs) at a region encompassing HERC5 gene

[40]

Glioblastoma

HERC5 upregulation

[41]

Acute myeloid leukemia

HERC5 downregulation

[42]

Oropharyngeal cancer

HERC5 gene expression is associated with overall survival

[43]

Non-small cell lung cancer

HERC5 promoter hypermethylation

[44]

Breast cancer

HERC5 upregulation

[45]

Hepatocellular carcinoma

Negative correlation of CCL20 overexpression and HERC5 mRNA levels

[46]

Reduced p53, p21 and Bax/Bcl-2 pathway activation

[47]

Ovarian cancer

HERC5 upregulation is associated with drug resistance

[48][49][48,49]

Osteosarcoma

Negative correlation of SOX18 overexpression and HERC5 mRNA levels

[18]

HERC6

Osteosarcoma

Negative correlation of SOX18 overexpression and HERC6 mRNA levels

[18]

Mutations in large HERCs have been found in leukemia  [10–13] and breast cancer [16,17]. Frameshift mutations in HERC2 have been found in both gastric and colorectal carcinomas with microsatellite instability [31]. The HERC2 locus has also been associated with both cutaneous melanoma and uveal melanoma, whereas the HERC1 locus has been found to be mutated in non-melanoma skin cancer [20,21,25,27]. Higher expression levels of HERCs are associated with better patient prognosis in kidney, head and neck, and pancreatic cancers when HERC1 expression levels are elevated, and in patients with renal cancer when HERC2 expression levels are elevated [50]. By contrast, the expression levels of HERC2 have been found to negatively correlate with patient survival in non-small-cell lung cancer [28]. In osteosarcoma, upregulation of the HERC2-binding protein SOX18 enhances cell proliferation, and it correlates with a reduction in both large and small HERC mRNA levels (Table 1) [18].