MYSM1/2A-DUB is an epigenetic regulator in human melanoma and contributes to tumor cell growth

Wilms, Christina; Kroeger, Carsten; Hainzl, Adelheid; Banik, Ishani; Bruno, Clara; Krikki, Ioanna; Farsam, Vida; Wlaschek, Meinhard; Gatzka, Martina

doi:10.18632/oncotarget.18617

Cited by 16 publications

(29 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, we conclude that two distinct mechanisms are involved to the rescue of the Mysm1 / bone phenotype in Mysm1 ‐/‐ p53 ‐/‐ DKO mice: differentiation of osteoblasts is inhibited because of Mysm1 deficiency, and increased Runx2 expression in MSCs is induced upon loss of p53, resulting in the overall prevalence of bone formation and a normal bone phenotype. Given the functional interaction of Mysm1 with the p19 Arf ‐p53 axis in certain tumors (36), future studies may address osteosarcoma occurrence in Mysm1 ‐/‐ p53 ‐/‐ DKO mice. Interestingly, some of the phenotypic anomalies caused by Mysm1 deficiency in mice were also found in humans with mutations in MYSM1 (37, 38), underlining the clinical relevance of the interaction of Mysm1 with tumor‐suppressor genes.…”

Section: Discussionmentioning

confidence: 99%

Loss of p53 compensates osteopenia in murine Mysml deficiency

et al. 2018

Self Cite

View full text Add to dashboard Cite

Histone modifications critically contribute to the epigenetic orchestration of bone homeostasis-in part, by modifying the access of transcription factors to specific genes involved in the osteogenic differentiation process of bone marrow mesenchymal stem cells (MSCs) and osteoblasts. Based on our previous finding that histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53 axis in hematopoiesis and tissue development, we analyzed the molecular basis of the skeletal phenotype of Mysm1-deficient mice and dissected the underlying p53-dependent and -independent mechanisms. Visible morphologic, skeletal deformations of young Mysm1-deficient mice-including a kinked and truncated tail and shortened long bones-were associated with osteopenia of long bones. On the cellular level, Mysm1-deficient primary osteoblasts displayed reduced potential to differentiate into mature osteoblasts, as indicated by decreased expression of osteogenic markers. Reduced osteogenic differentiation capacity of Mysm1-deficient osteoblasts was accompanied by an impaired induction of osteogenic transcription factor Runx2. Osteogenic differentiation of Mysm1 MSCs, however, was not compromised in vitro. In line with defective hematopoietic development of Mysm1-deficient mice, Mysm1 osteoclasts had reduced resorption activity and were more prone to apoptosis in TUNEL assays. Skeletal alterations and osteopenia of Mysm1-deficient mice were phenotypically completely rescued by simultaneous ablation of p53 in p53Mysm1 double-deficient mice-although p53 deficiency did not restore Runx2 expression in Mysm1 osteoblasts on the molecular level but, instead, enhanced proliferation and osteogenic differentiation of MSCs. In summary, our results demonstrate novel roles for Mysm1 in osteoblast differentiation and osteoclast formation, resulting in osteopenia in Mysm1-deficient mice that could be abrogated by the loss of p53 from increased osteogenic differentiation of Mysm1p53 MSCs.-Haffner-Luntzer, M., Kovtun, A., Fischer, V., Prystaz, K., Hainzl, A., Kroeger, C. M., Krikki, I., Brinker, T. J., Ignatius, A., Gatzka, M. Loss of p53 compensates osteopenia in murine Mysm1 deficiency.

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of p53 compensates osteopenia in murine Mysml deficiency

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Increased γH2AX levels were also seen in hematopoietic cells from MYSM1-deficiency syndrome patients [27], suggesting increased levels of DNA damage. Furthermore, Mysm1-deficient mice were hypersensitive to whole-body ionizing radiation [34] and accumulated increased levels of DNA damage in UV-treated skin [40]. We also observed spontaneous accrual of γH2AX in Mysm1-deficient mouse hematopoietic stem and progenitor cells [19], however, this was alleviated in Mysm1 -/-p53 -/and Mysm1 -/-Puma -/double-knockout mouse strains [41], suggesting that it was a result of elevated cell apoptosis, rather than of a DNA repair deficiency.…”

Section: Putative Roles Of Mysm1 In Dna Repairmentioning

confidence: 99%

“…Thus, MYSM1 was originally characterized as a positive regulator of androgen receptor target gene expression in human prostate cancer cell lines [7]. Furthermore, elevated MYSM1 protein levels were observed in human melanomas compared to normal melanocytes, and Mysm1-knockdown impaired the proliferation and survival of melanoma cell lines [40]. Moreover, increased MYSM1 protein levels were also seen in human colorectal tumors, compared to adjacent normal mucosa [60].…”

Section: Possible Roles Of Mysm1 In Cancermentioning

confidence: 99%

Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review

Fiore

Liang

Lin

et al. 2020

IJMS

View full text Add to dashboard Cite

MYSM1 has emerged as an important regulator of hematopoietic stem cell function, blood cell production, immune response, and other aspects of mammalian physiology. It is a metalloprotease family protein with deubiquitinase catalytic activity, as well as SANT and SWIRM domains. MYSM1 normally localizes to the nucleus, where it can interact with chromatin and regulate gene expression, through deubiquitination of histone H2A and non-catalytic contacts with other transcriptional regulators. A cytosolic form of MYSM1 protein was also recently described and demonstrated to regulate signal transduction pathways of innate immunity, by promoting the deubiquitination of TRAF3, TRAF6, and RIP2. In this work we review the current knowledge on the molecular mechanisms of action of MYSM1 protein in transcriptional regulation, signal transduction, and potentially other cellular processes. The functions of MYSM1 in different cell types and aspects of mammalian physiology are also reviewed, highlighting the key checkpoints in hematopoiesis, immunity, and beyond regulated by MYSM1. Importantly, mutations in MYSM1 in human were recently linked to a rare hereditary disorder characterized by leukopenia, anemia, and other hematopoietic and developmental abnormalities. Our growing knowledge of MYSM1 functions and mechanisms of actions sheds important insights into its role in mammalian physiology and the etiology of the MYSM1-deficiency disorder in human.

show abstract

“…To follow up on our previous data revealing critical roles of Mysm1 in HSC, immune cells, and in melanocyte specification [ 16 , 22 ], we set out to determine Mysm1 expression in the skin compartment of different age groups of wild-type C57BL/6 mice using Mysm1 tm1a (MKO) mice as controls. In accordance with a potential role of Mysm1 in skin development, Mysm1 protein expression was highest in newborn mice (p1–3) ( Figure 1 A)—with successive decline upon aging ( Figure 1 A–D).…”

Section: Resultsmentioning

confidence: 99%

2A-DUB/Mysm1 Regulates Epidermal Development in Part by Suppressing p53-Mediated Programs

Wilms

Krikki

Hainzl

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

Development and homeostasis of the epidermis are governed by a complex network of sequence-specific transcription factors and epigenetic modifiers cooperatively regulating the subtle balance of progenitor cell self-renewal and terminal differentiation. To investigate the role of histone H2A deubiquitinase 2A-DUB/Mysm1 in the skin, we systematically analyzed expression, developmental functions, and potential interactions of this epigenetic regulator using Mysm1-deficient mice and skin-derived epidermal cells. Morphologically, skin of newborn and young adult Mysm1-deficient mice was atrophic with reduced thickness and cellularity of epidermis, dermis, and subcutis, in context with altered barrier function. Skin atrophy correlated with reduced proliferation rates in Mysm1−/− epidermis and hair follicles, and increased apoptosis compared with wild-type controls, along with increases in DNA-damage marker γH2AX. In accordance with diminished α6-Integrinhigh+CD34+ epidermal stem cells, reduced colony formation of Mysm1−/− epidermal progenitors was detectable in vitro. On the molecular level, we identified p53 as potential mediator of the defective Mysm1-deficient epidermal compartment, resulting in increased pro-apoptotic and anti-proliferative gene expression. In Mysm1−/−p53−/− double-deficient mice, significant recovery of skin atrophy was observed. Functional properties of Mysm1−/− developing epidermis were assessed by quantifying the transepidermal water loss. In summary, this investigation uncovers a role for 2A-DUB/Mysm1 in suppression of p53-mediated inhibitory programs during epidermal development.

show abstract

MYSM1/2A-DUB is an epigenetic regulator in human melanoma and contributes to tumor cell growth

Cited by 16 publications

References 38 publications

Loss of p53 compensates osteopenia in murine Mysml deficiency

Loss of p53 compensates osteopenia in murine Mysml deficiency

Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review

2A-DUB/Mysm1 Regulates Epidermal Development in Part by Suppressing p53-Mediated Programs

Contact Info

Product

Resources

About