The Histone Methyltransferase G9a Promotes Cholangiocarcinogenesis Through Regulation of the Hippo Pathway Kinase LATS2 and YAP Signaling Pathway

Ma, Wenbo; Han, Chang; Zhang, Jinqiang; Song, Kyoungsub; Chen, Weina; Kwon, Hyunjoo; Wu, Tong

doi:10.1002/hep.31141

Cited by 35 publications

(25 citation statements)

References 50 publications

(125 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While UNC0642 treatment of 22Rv1 cells reduced H3K9me2 level, it failed to reverse F133V-induced repression of FOXO3, GATA5, and NDRG1 gene expression at both protein and mRNA levels although as expected, UNC0642 blocked repression of LATS2, a gene reportedly regulated by the GLP/G9a HMTase activity 44 in F133V-expressing cells (Supplementary Fig. 7g, h).…”

Section: Spop Mutations Induce Tsg Methylation Via Elevated Glp Andsupporting

confidence: 62%

SPOP mutation induces DNA methylation via stabilizing GLP/G9a

et al. 2021

View full text Add to dashboard Cite

Mutations in SPOP E3 ligase gene are reportedly associated with genome-wide DNA hypermethylation in prostate cancer (PCa) although the underlying mechanisms remain elusive. Here, we demonstrate that SPOP binds and promotes polyubiquitination and degradation of histone methyltransferase and DNMT interactor GLP. SPOP mutation induces stabilization of GLP and its partner protein G9a and aberrant upregulation of global DNA hypermethylation in cultured PCa cells and primary PCa specimens. Genome-wide DNA methylome analysis shows that a subset of tumor suppressor genes (TSGs) including FOXO3, GATA5, and NDRG1, are hypermethylated and downregulated in SPOP-mutated PCa cells. DNA methylation inhibitor 5-azacytidine effectively reverses expression of the TSGs examined, inhibits SPOP-mutated PCa cell growth in vitro and in mice, and enhances docetaxel anti-cancer efficacy. Our findings reveal the GLP/G9a-DNMT module as a mediator of DNA hypermethylation in SPOP-mutated PCa. They suggest that SPOP mutation could be a biomarker for effective treatment of PCa with DNA methylation inhibitor alone or in combination with taxane chemotherapeutics.

show abstract

Section: Spop Mutations Induce Tsg Methylation Via Elevated Glp Andsupporting

confidence: 62%

SPOP mutation induces DNA methylation via stabilizing GLP/G9a

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The compromised Hippo signaling results in various cancers including CCA. 37 , 38 Hippo kinase cascades can be regulated by other kinases, such as MAP4K, Mob, or TAO. 39 , 40 , 41 However, some proteins without kinase activity can indirectly modulate this kinase cascade.…”

Section: Discussionmentioning

confidence: 99%

Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis

Zhu

Qian

Han

et al. 2021

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

Tumor metastasis is one of the major factors for the high mortality in cholangiocarcinoma (CCA), but its underlying mechanisms are not fully understood. Here, we report that Piezo-type mechanosensitive ion channel component 1 (Piezo 1) is detected to be significantly upregulated in CCA tissues, which is linked to a poor prognosis in patients, suggesting that Piezo 1 may act in a pro-metastatic role in CCA development. Piezo 1 is activated through 20% simulated physiological stretch, and deleting Piezo 1 impedes epithelial-to-mesenchymal transition (EMT) of CCA cells, as well as impairing their metastatic capacity in vitro and in vivo . Mechanistically, the activation of Piezo 1 results in large amounts of Yes-associated protein 1 (YAP) translocated into the nucleus from the cytoplasm, and thus the motility of CCA cells is significantly increased. These findings indicate that mechanical stimulation induces Piezo 1 activation, which might be involved in CCA metastasis via the Hippo/YAP signaling axis. Therefore, Piezo 1 and its downstream effectors may be a novel therapeutic target for CCA treatment.

show abstract

“…Moreover, Andrea Bisso et al, demonstrated that YAP mediated the cooperation between MYC and b-Catenin and facilitated liver tumorigenesis (42). Wenbo Ma et al, also found that histone methyltransferase G9a promoted cholangiocarcinogenesis via YAP (43). Importantly, our previous work suggested that the function of YAP largely relied on its Thr241 O-GlcNAcylation (18).…”

Section: Discussionmentioning

confidence: 75%

N-Myristoylation by NMT1 Is POTEE-Dependent to Stimulate Liver Tumorigenesis via Differentially Regulating Ubiquitination of Targets

Zhu

Wang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

BackgroundA tremendous amount of studies have suggested that post-translational modifications (PTMs) play pivotal roles during tumorigenesis. Compared to other PTMs, lipid modification is less studied. Recently, N-myristoylation, one type of lipid modification, has been paid attention to the field of cancer. However, whether and how N-myristoylation exerts its roles in liver tumorigenesis still remains unclear.MethodsParallel reaction monitoring (PRM) was conducted to evaluate the expression of protein modification enzymes in paired tissues. Liver conditionally knocking NMT1 out mice model was used to assess the critical roles of N-myristoylation during liver tumorigenesis. Proteomics isobaric tags for relative and absolute quantification (iTraq) was performed to identify proteins that changed while NMT1 was knocked down. The click chemistry assay was used to evaluate the N-myristoylation levels of proteins.ResultsHere, N-myristolyation and its enzyme NMT1, but not NMT2, were found to be critical in liver cancer. Two categories of proteins, i.e., N-myristolyation down-regulated proteins (NDP, including LXN, RPL29, and FAU) and N-myristolyation up-regulated proteins (NUP, including AHSG, ALB, and TF), were revealed negatively and positively regulated by NMT1, respectively. Both NDP and NUP could be N-myristolyated by NMT1 indispensable of POTEE. However, N-myristolyation decreased and increased stability of NDP and NUP, respectively. Mechanistically, NDP-specific binding protein RPL7A facilitated HIST1H4H, which has ubiquitin E3 ligase function, to ubiquitinate NDP. By contrast, NUP-specific binding protein HBB prevented NUP from ubiquitination by HIST1H4H. Notably, function of RPL7A and HBB was all NMT1-dependent. Moreover, NDP suppressed while NUP stimulated transformative phenotypes. Clinically, higher levels of NMT1 and NUP with lower levels of NDP had worse prognostic outcome.ConclusionCollectively, N-myristolyation by NMT1 suppresses anti-tumorigenic NDP, whereas it stimulates pro-tumorigenic NUP by interfering their ubiquitination to finally result in a pro-tumorigenic outcome in liver cancer. Targeting N-myristolyation and NMT1 might be helpful to treat liver cancer.

show abstract

The Histone Methyltransferase G9a Promotes Cholangiocarcinogenesis Through Regulation of the Hippo Pathway Kinase LATS2 and YAP Signaling Pathway

Cited by 35 publications

References 50 publications

SPOP mutation induces DNA methylation via stabilizing GLP/G9a

SPOP mutation induces DNA methylation via stabilizing GLP/G9a

Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis

N-Myristoylation by NMT1 Is POTEE-Dependent to Stimulate Liver Tumorigenesis via Differentially Regulating Ubiquitination of Targets

Contact Info

Product

Resources

About