Abstract:Tissue Transglutaminases (TGs) are crosslinking enzymes with pleiotropic functions that have been linked to the development and progression of numerous cancers, with a recent focus on their ability to remodel the tumor microenvironment. Although several pieces of evidence demonstrated their importance in the regulation of the major signaling pathways that control oncogenesis, the correlation between TGs with clinical and pathological features remains controversial and to be further explored. Moreover, an asses… Show more
“…1g ). These results are in line with our previous research in which we outlined a novel promising positive clinical value for TG2 in skin cancer [ 21 ], though the molecular mechanism behind TG2 function was not fully elucidated. Fig.…”
Section: Resultssupporting
confidence: 90%
“…Still, the part played by TG2 in EMT processes has already been highlighted in several contexts [ 20 ]. To shed light on the controversies regarding its role in cancer disease, we performed bioinformatics analyses on public cancer datasets which unveiled that the prognostic role of TG2 is generally negative, except for SKCM, the only tumor type in which TG2 expression is associated with a positive prognosis, as we already mentioned in Muccioli et al, 2022 [ 21 ]. In the same article, we reported that TG2 expression was upregulated in metastatic samples compared to primary tumors.…”
Section: Discussionmentioning
confidence: 99%
“…However, the role of TG2 in cancer is still controversial and far to be fully elucidated, since it has been reported as both a potential tumour-suppressor and a tumour-promoting factor [ 20 ]. Certainly, the function of TG2 is tissue-specific [ 20 ]: in particular, we recently demonstrated by analysing public transcriptomic databases a correlation between TG2 expression, good SKCM overall survival, and a positive regulation of immune response in SKCM [ 21 ]. These results indicate that TG2 expression might serve as a good prognostic factor in patients with SKCM, as well as a biomarker for the therapeutic strategy to be adopted [ 21 ].…”
Skin cutaneous melanoma (SKCM) is the deadliest form of skin cancer due to its high heterogeneity that drives tumor aggressiveness. Melanoma plasticity consists of two distinct phenotypic states that co-exist in the tumor niche, the proliferative and the invasive, respectively associated with a high and low expression of MITF, the master regulator of melanocyte lineage. However, despite efforts, melanoma research is still far from exhaustively dissecting this phenomenon. Here, we discovered a key function of Transglutaminase Type-2 (TG2) in regulating melanogenesis by modulating MITF transcription factor expression and its transcriptional activity. Importantly, we demonstrated that TG2 expression affects melanoma invasiveness, highlighting its positive value in SKCM. These results suggest that TG2 may have implications in the regulation of the phenotype switching by promoting melanoma differentiation and impairing its metastatic potential. Our findings offer potential perspectives to unravel melanoma vulnerabilities via tuning intra-tumor heterogeneity.
“…1g ). These results are in line with our previous research in which we outlined a novel promising positive clinical value for TG2 in skin cancer [ 21 ], though the molecular mechanism behind TG2 function was not fully elucidated. Fig.…”
Section: Resultssupporting
confidence: 90%
“…Still, the part played by TG2 in EMT processes has already been highlighted in several contexts [ 20 ]. To shed light on the controversies regarding its role in cancer disease, we performed bioinformatics analyses on public cancer datasets which unveiled that the prognostic role of TG2 is generally negative, except for SKCM, the only tumor type in which TG2 expression is associated with a positive prognosis, as we already mentioned in Muccioli et al, 2022 [ 21 ]. In the same article, we reported that TG2 expression was upregulated in metastatic samples compared to primary tumors.…”
Section: Discussionmentioning
confidence: 99%
“…However, the role of TG2 in cancer is still controversial and far to be fully elucidated, since it has been reported as both a potential tumour-suppressor and a tumour-promoting factor [ 20 ]. Certainly, the function of TG2 is tissue-specific [ 20 ]: in particular, we recently demonstrated by analysing public transcriptomic databases a correlation between TG2 expression, good SKCM overall survival, and a positive regulation of immune response in SKCM [ 21 ]. These results indicate that TG2 expression might serve as a good prognostic factor in patients with SKCM, as well as a biomarker for the therapeutic strategy to be adopted [ 21 ].…”
Skin cutaneous melanoma (SKCM) is the deadliest form of skin cancer due to its high heterogeneity that drives tumor aggressiveness. Melanoma plasticity consists of two distinct phenotypic states that co-exist in the tumor niche, the proliferative and the invasive, respectively associated with a high and low expression of MITF, the master regulator of melanocyte lineage. However, despite efforts, melanoma research is still far from exhaustively dissecting this phenomenon. Here, we discovered a key function of Transglutaminase Type-2 (TG2) in regulating melanogenesis by modulating MITF transcription factor expression and its transcriptional activity. Importantly, we demonstrated that TG2 expression affects melanoma invasiveness, highlighting its positive value in SKCM. These results suggest that TG2 may have implications in the regulation of the phenotype switching by promoting melanoma differentiation and impairing its metastatic potential. Our findings offer potential perspectives to unravel melanoma vulnerabilities via tuning intra-tumor heterogeneity.
“…TG2 expression was previously reported to be altered in several tumors [ 17 , 26 , 41 , 42 , 43 ]. An investigation of TG2 expression levels in patients affected by different types of cancers was conducted using the publicly available GEPIA (Gene Expression Profiling Interactive Analysis) database [ 27 ].…”
Section: Tg2 In Cancermentioning
confidence: 99%
“…Thus, TG2 KO melanoma cells are less differentiated, unable to pigment, and form larger metastases when injected in vivo [ 57 ]. Moreover, TG2 is a positive prognostic factor as its knock-out (KO) seems to be correlated with the impairment of the immune cell recruitment and activation [ 43 ].…”
Transglutaminase type 2 (TG2) is the most ubiquitously expressed and well characterized member of the transglutaminase family. It is a ubiquitous multifunctional enzyme implicated in the regulation of several cellular pathways that support the survival, death, and general homeostasis of eukaryotic cells. Due to its multiple localizations both inside and outside the cell, TG2 participates in the regulation of many crucial intracellular signaling cascades in a tissue- and cell-specific manner, making this enzyme an important player in disease development and progression. Moreover, TG2 is capable of modulating the tumor microenvironment, a process of dynamic tissue remodeling and biomechanical events, resulting in changes which influence tumor initiation, growth, and metastasis. Even if generally related to the Ca2+-dependent post-translational modification of proteins, a number of different biological functions have been ascribed to TG2, like those of a peptide isomerase, protein kinase, guanine nucleotide binder, and cytosolic–nuclear translocator. With respect to cancer, TG2′s role is controversial and highly debated; it has been described both as an anti- and pro-apoptotic factor and is linked to all the processes of tumorigenesis. However, numerous pieces of evidence support a tissue-specific role of TG2 so that it can assume both oncogenic and tumor-suppressive roles.
SummaryPLK1 inhibitors are emerging anti-cancer agents being tested in monotherapy and combination therapies for various cancers. Although PLK1 inhibition in experimental models shows potent antitumor effects, translation to the clinic has been hampered by low antitumor activity and tumor relapse. Here, we report the identification of mitochondrial protein signatures that determine sensitivity to approaches targeting PLK1 in human melanoma cell lines. In response to PLK1 inhibition or gene silencing, resistant cells adopt a pro-inflammatory and dedifferentiated phenotype, while sensitive cells engage apoptosis. Mitochondrial DNA depletion and silencing of the ABCD1 transporter sensitize cells to PLK1 inhibition and attenuate the associated pro-inflammatory response. We also found that non-selective inhibitors of the p90 ribosomal S6 kinase (RSK) exert their anti-proliferative and pro-inflammatory effects via PLK1 inhibition. This work reveals overlooked impacts of PLK1 on phenotype switching and suggests that mitochondrial precision medicine can help improve response to targeted therapies.
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