Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer

Abstract

Mitogen-activated protein kinases (MAPKs) are the main regulators of cellular proliferation, growth, and survival in physiological or pathological conditions. Aberrant MAPK signaling plays a pivotal role in carcinogenesis, which leads to development and progression of human cancer. Dual-specificity phosphatase 6 (DUSP6), a member of the MAPK phosphatase family, interacts with specifically targeted extracellular signal-regulated kinase 1/2 via negative feedback regulation in the MAPK pathway of mammalian cells. This phosphatase functions in a dual manner, pro-oncogenic or tumor-suppressive, depending on the type of cancer. To date, the tumor-suppressive role of DUSP6 has been demonstrated in pancreatic cancer, non-small cell lung cancer, esophageal squamous cell and nasopharyngeal carcinoma, and ovarian cancer. Its pro-oncogenic role has been observed in human glioblastoma, thyroid carcinoma, breast cancer, and acute myeloid carcinoma. Both roles of DUSP6 have been documented in malignant melanoma depending on the histological subtype of the cancer. Loss- or gain-of-function effects of DUSP6 in these cancers highlights the significance of this phosphatase in carcinogenesis. Development of methods that use the DUSP6 gene as a therapeutic target for cancer treatment or as a prognostic factor for diagnosis and evaluation of cancer treatment outcome has great potential. This review focuses on molecular characteristics of the DUSP6 gene and its role in cancers in the purview of development, progression, and cancer treatment outcome.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…It has been demonstrated that MEK variants can contribute to resistant phenotype of melanoma cells, as (i) cells harboring MEK2 F57C substitution exerted phospho-MEK2 low /phospho-ERK1/2 high signature [85], (ii) regrowth of melanoma after initial response to MEK inhibitor has been attributed to MEK1 P124L variant [86], and (iii) untreated patients harboring MEK1 P124S or MEK1 P124L variants faced rapid progression upon administration of BRAF inhibitor [13]. Another way to keep ERK1/2 active is to alter the activity of DUSP6, a specific phosphatase of ERK1/2 [87,88]. While inverse association between the levels of p-ERK1/2 and DUSP6 was found in drug-naïve cells [23], DUSP6 suppression in resistant cells was not consistently associated with an increase in phospho-ERK1/2 level, suggesting that downregulation of DUSP6 was not the only mechanism reactivating ERK1/2.…”

Understanding seasonal weight loss tolerance in dairy goats: a transcriptomics approach

“…DUSP1 , DUSP6 and LOC102190323 ). Gene DUSP is involved in the suppression of tumorigenic cell proliferation [ 59 ], a consequence of decreased cellular proliferation caused by the mammary gland involution. Gene LOC102190323 is involved in DNA damage response [ 60 ].…”

DUSP6 protects murine podocytes from high glucose‑induced inflammation and apoptosis

“…Accumulating research has demonstrated that DUSPs serve as tumor suppressors or oncogenes by regulating cell proliferation, migration and apoptosis ( 12 – 14 ), which ultimately influences and determines the fate of specific types of cancer ( 19 ). A previous study demonstrated that DUSP1 was tightly associated with a glucose metabolism disorder and glomerular apoptosis via interrupting JNK-mitochondrial fission factor-mitochondrial fission, reducing hyperglycemia-regulated mitochondrial damage and improving renal function ( 33 ).…”

“…DUSPs have been reported to mediate cell proliferation, migration and apoptosis ( 12 – 14 ). Accumulating evidence has demonstrated that DUSP6 serves a role in multiple types of cancer, such as glioblastoma, breast cancer and pancreatic cancer, where it displays either an oncogenic or tumor-suppressive function ( 15 – 18 ), which ultimately affects and determines the fate of a specific cancer ( 19 ). Another previous study suggested that DUSP6 inhibition enhanced T cell-modulated immunity in end-stage renal disease ( 20 ).…”