ULK3-dependent activation of GLI1 promotes DNMT3A expression upon autophagy induction

González-Rodríguez, Patricia; Cheray, Mathilde; Keane, Lily; Engskog-Vlachos, Pinelopi; Joseph, Bertrand

doi:10.1080/15548627.2022.2039993

Cited by 13 publications

(13 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Epigenetic Modifications and Autophagy-related Diseasesmentioning

confidence: 99%

“…46 Meanwhile, ULK3-dependent activation of GLI1 contributes to upregulation of DNMT3A gene expression upon autophagy induction, thereby bringing additional understanding of the long-term effect of autophagy induction and a possible mechanism for its decline upon aging, pathological conditions, or in response to treatment interventions. 47 Histone methylation G9a/EHMT2. G9a/ Euchromatic histone lysine methyltransferase 1 (EHMT2) catalyzes methylation of histone 3 at lysine 9 (H3K9me1, H3K9me2, and H3K9me3) and is frequently overexpressed in various cancers, including glioma, gastric cancer, and lung cancer.…”

Section: Autophagy and Its Main Regulatory Mechanismmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Shu

Han

et al. 2023

Sig Transduct Target Ther

View full text Add to dashboard Cite

Autophagy is a conserved lysosomal degradation pathway where cellular components are dynamically degraded and re-processed to maintain physical homeostasis. However, the physiological effect of autophagy appears to be multifaced. On the one hand, autophagy functions as a cytoprotective mechanism, protecting against multiple diseases, especially tumor, cardiovascular disorders, and neurodegenerative and infectious disease. Conversely, autophagy may also play a detrimental role via pro-survival effects on cancer cells or cell-killing effects on normal body cells. During disorder onset and progression, the expression levels of autophagy-related regulators and proteins encoded by autophagy-related genes (ATGs) are abnormally regulated, giving rise to imbalanced autophagy flux. However, the detailed mechanisms and molecular events of this process are quite complex. Epigenetic, including DNA methylation, histone modifications and miRNAs, and post-translational modifications, including ubiquitination, phosphorylation and acetylation, precisely manipulate gene expression and protein function, and are strongly correlated with the occurrence and development of multiple diseases. There is substantial evidence that autophagy-relevant regulators and machineries are subjected to epigenetic and post-translational modulation, resulting in alterations in autophagy levels, which subsequently induces disease or affects the therapeutic effectiveness to agents. In this review, we focus on the regulatory mechanisms mediated by epigenetic and post-translational modifications in disease-related autophagy to unveil potential therapeutic targets. In addition, the effect of autophagy on the therapeutic effectiveness of epigenetic drugs or drugs targeting post-translational modification have also been discussed, providing insights into the combination with autophagy activators or inhibitors in the treatment of clinical diseases.

show abstract

Section: Epigenetic Modifications and Autophagy-related Diseasesmentioning

confidence: 99%

Section: Autophagy and Its Main Regulatory Mechanismmentioning

confidence: 99%

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Shu

Han

et al. 2023

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…ULK3 contains N-terminal KD and microtubule interacting and trafficking (MIT) domains at C-terminus [ 28 ]. ULK3 is involved in the autophagy during senescence [ 29 , 30 ]. In resting state, N-terminal domain of ULK3 binds to suppressor of fused protein (SUFU) [ 31 ], and dissociation of ULK3 generates transcriptional activators, glioma-associated oncogene homolog zinc finger proteins (GLIs), key mediators in the Sonic hedgehog signaling [ 32 ].…”

Section: An Overview Of Ulks In Autophagy and Cancersmentioning

confidence: 99%

“…In resting state, N-terminal domain of ULK3 binds to suppressor of fused protein (SUFU) [ 31 ], and dissociation of ULK3 generates transcriptional activators, glioma-associated oncogene homolog zinc finger proteins (GLIs), key mediators in the Sonic hedgehog signaling [ 32 ]. ULK3-dependent GLI1 contributes to the transcriptional upregulation of DNA methyltransferase 3-alpha expression which is associated with autophagy induction [ 30 ]. ULK3 is upregulated in cancer-associated fibroblasts (CAFs) derived from head and neck squamous cell carcinomas, prostate cancer, and breast cancer.…”

Section: An Overview Of Ulks In Autophagy and Cancersmentioning

confidence: 99%

Small Molecule Inhibitors for Unc-51-like Autophagy-Activating Kinase Targeting Autophagy in Cancer

Karmacharya

Jung

2023

IJMS

View full text Add to dashboard Cite

Autophagy is a cellular process that removes damaged components of cells and recycles them as biochemical building blocks. Autophagy can also be induced to protect cells in response to intra- and extracellular stresses, including damage to cellular components, nutrient deprivation, hypoxia, and pathogenic invasion. Dysregulation of autophagy has been attributed to various diseases. In particular, autophagy protects cancer cells by supporting tumor cell survival and the development of drug resistance. Understanding the pathophysiological mechanisms of autophagy in cancer has stimulated the research on discovery and development of specific inhibitors targeting various stages of autophagy. In recent years, Unc-51-like autophagy-activating kinase (ULK) inhibitors have become an attractive strategy to treat cancer. This review summarizes recent discoveries and developments in small-molecule ULK inhibitors and their potential as anticancer agents. We focused on structural features, interactions with binding sites, and biological effects of these inhibitors. Overall, this review will provide guidance for using ULK inhibitors as chemical probes for autophagy in various cancers and developing improved ULK inhibitors that would enhance therapeutic benefits in the clinic.

show abstract

“…[10][11][12][13]). The epigenetic and transcriptional regulation of autophagy can contribute to both short-term and long-term effects on this biological process [14][15][16][17][18]. A yeast DNA damage-responsive transcriptional repressor (Rph1) and its mammalian homolog KDM4A (lysine demethylase 4A), belong to the Jumonji C (JmjC)-domain-containing histone demethylase protein family.…”

Section: Introductionmentioning

confidence: 99%

SETD2 transcriptional control of ATG14L/S isoforms regulates autophagosome–lysosome fusion

et al. 2022

Self Cite

View full text Add to dashboard Cite

Macroautophagy/autophagy is an evolutionarily conserved and tightly regulated catabolic process involved in the maintenance of cellular homeostasis whose dysregulation is implicated in several pathological processes. Autophagy begins with the formation of phagophores that engulf cytoplasmic cargo and mature into double-membrane autophagosomes; the latter fuse with lysosomes/vacuoles for cargo degradation and recycling. Here, we report that yeast Set2, a histone lysine methyltransferase, and its mammalian homolog, SETD2, both act as positive transcriptional regulators of autophagy. However, whereas Set2 regulates the expression of several autophagy-related (Atg) genes upon nitrogen starvation, SETD2 effects in mammals were found to be more restricted. In fact, SETD2 appears to primarily regulate the differential expression of protein isoforms encoded by the ATG14 gene. SETD2 promotes the expression of a long ATG14 isoform, ATG14L, that contains an N-terminal cysteine repeats domain, essential for the efficient fusion of the autophagosome with the lysosome, that is absent in the short ATG14 isoform, ATG14S. Accordingly, SETD2 loss of function decreases autophagic flux, as well as the turnover of aggregation-prone proteins such as mutant HTT (huntingtin) leading to increased cellular toxicity. Hence, our findings bring evidence to the emerging concept that the production of autophagy-related protein isoforms can differentially affect core autophagy machinery bringing an additional level of complexity to the regulation of this biological process in more complex organisms.

show abstract

ULK3-dependent activation of GLI1 promotes DNMT3A expression upon autophagy induction

Cited by 13 publications

References 59 publications

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Small Molecule Inhibitors for Unc-51-like Autophagy-Activating Kinase Targeting Autophagy in Cancer

SETD2 transcriptional control of ATG14L/S isoforms regulates autophagosome–lysosome fusion

Contact Info

Product

Resources

About