Cystathionase mediates senescence evasion in melanocytes and melanoma cells

Abstract

The development of malignant melanoma is a highly complex process, which is still poorly understood. A majority of human melanomas are found to express a few oncogenic proteins, such as mutant RAS and BRAF variants. However, these oncogenes are also found in nevi, and it is now a well-accepted fact that their expression alone leads to senescence. This renders the understanding of senescence escape mechanisms an important point to understand tumor development. Here, we approached the question of senescence evasion by expressing the transcription factor v-myc myelocytomatosis viral oncogene homolog (c-MYC), which is known to act synergistically with many oncogenes, in melanocytes. We observed that MYC drives the evasion of reactive-oxygen stress-induced melanocyte senescence, caused by activated receptor tyrosine kinase signaling. Conversely, MIZ1, the growth suppressing interaction partner of MYC, is involved in mediating melanocyte senescence. Both, MYC overexpression and Miz1 knockdown led to a strong reduction of endogenous reactive-oxygen species (ROS), DNA damage and senescence. We identified the cystathionase (CTH) gene product as mediator of the ROS-related MYC and MIZ1 effects. Blocking CTH enzymatic activity in MYC-overexpressing and Miz1 knockdown cells increased intracellular stress and senescence. Importantly, pharmacological inhibition of CTH in human melanoma cells also reconstituted senescence in the majority of cell lines, and CTH knockdown reduced tumorigenic effects such as proliferation, H2O2 resistance and soft agar growth. Thus, we identified CTH as new MYC target gene with an important function in senescence evasion.

Evaluation of tubulin β‐3 as a novel senescence‐associated gene in melanocytic malignant transformation

“…Consistent with recent findings, we revealed that growth‐promoting signaling pathways, such as E2F targets (Park et al., ), mTORC1 signaling (Damsky et al., ), and MYC targets (Leikam et al., ), are enriched in both young melanocytes and melanomas. Furthermore, a concordant gene expression difference as derived from the senescence model system is found between melanomas and nevi.…”

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer

“…47 One widely accepted hypothesis proposes that the accumulation of oxidative damage arising from endogenously produced ROS leads to cellular senescence, tissue degeneration and age-related disorders. [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] In contrast, ΔNp63 has a crucial role in maintaining the proliferative potential of epithelial cells and counteracting cellular senescence and organismal ageing. 40,[63][64][65] Therefore, the molecular mechanism through which ΔNp63 exerts its antisenescence/antiageing functions may be mediated, at least in part, by the activation of antioxidant genes, including CYGB.…”

Hydrogen sulfide and dermatological diseases

“…DATS (25 μM) inhibited growth of both cell types by increasing intracellular ROS generation and cytosolic Ca 2+ mobilization and by decreasing mitochondrial membrane potential without having significant effects on normal keratinocyte HaCaT cell growth. In a more recent study from the same group (Wang, Chu, Hsieh, & Sheen, 2017), DATS (at 10 and 25 μM) Although the antiproliferative effects of increased production of CSE-derived H 2 S were reported, the study from Leikam et al (2014) showed that CSE overexpression in tumour cells had pro-tumorigenic functions and that the blockade of CSE enzymic activity in human melanoma cells not only reduced proliferation rates and enhanced cell sensitivity to H 2 O 2 but also induced senescence. Therefore, the role of CSE-derived H 2 S on tumour regulation cannot be absolutely defined as this may be related to the actual amounts of H 2 S produced by this enzyme in the different cell systems studied, bearing in mind the U-shaped pattern of the dose-concentration-response curves that H 2 S usually shows in many experimental models and systems.…”