Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications

Zou, Ling; Liao, Minru; Zhen, Yongqi; Zhu, Shiou; Chen, Xiya; Zhang, Jin; Hao, Yue; Liu, Bo

doi:10.1016/j.apsb.2022.06.004

Cited by 31 publications

(22 citation statements)

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“…Hence, ULK1 may be a crucial downstream target of DDX21. Interestingly, ULK1 was a sort of serine/threonine kinase, which was a well‐known autophagic initiator, extensively involved in human diseases especially tumours 27 …”

Section: Resultsmentioning

confidence: 99%

“…ULK1 is a well‐known autophagic initiator extensively involved in tumorigenesis 27 . As the terminal effector for SEs‐IGF2BP2/3‐DDX21 axis, further mechanisms of ULK1 merited our attention.…”

Section: Discussionmentioning

confidence: 99%

“…38 Thus, ULK1 may sustain chromosome instability to dampen curative effects in AML. As high selective inhibitors were available for ULK1, 27 future studies may focus on the clinical practice of DDX21-related axis based on ULK1 inhibition. Indeed, there were some limitations in the current work.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, ULK1 was a sort of serine/threonine kinase, which was a wellknown autophagic initiator, extensively involved in human diseases especially tumours. 27 Additionally, ChIP-qPCR assays demonstrated the respective occupancy of DDX21 and YBX1 on ULK1 (Figure 4I,J and Figure S10A-F). Knockdown of YBX1 induced the suppression of ULK1 expression (Figure 4K,L).…”

Section: Ddx21 Triggered Ulk1 Expression Via Recruiting Transcription...mentioning

confidence: 96%

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m⁶A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia

Zhao,

Zhou,

Qian

et al. 2024

Clinical & Translational Med

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BackgroundAcute myeloid leukaemia (AML) is a haematological malignancy with unfavourable prognosis. Despite the effectiveness of chemotherapy and targeted therapy, relapse or drug resistance remains a major threat to AML patients. N6‐methyladenosine (m6A) RNA methylation and super‐enhancers (SEs) are extensively involved in the leukaemogenesis of AML. However, the potential relationship between m6A and SEs in AML has not been elaborated.MethodsChromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analysed to search SE‐related genes. The mechanisms of m6 A‐binding proteins IGF2BP2 and IGF2BP3 on DDX21 were explored via methylated RNA immunoprecipitation (MeRIP) assays, RNA immunoprecipitation (RIP) assays and luciferase reporter assays. Then we elucidated the roles of DDX21 in AML through functional assays in vitro and in vivo. Finally, co‐immunoprecipitation (Co‐IP) assays, RNA sequencing and ChIP assays were performed to investigate the downstream mechanisms of DDX21.ResultsWe identified two SE‐associated transcripts IGF2BP2 and IGF2BP3 in AML. High enrichment of H3K27ac, H3K4me1 and BRD4 was observed in IGF2BP2 and IGF2BP3, whose expression were driven by SE machinery. Then IGF2BP2 and IGF2BP3 enhanced the stability of DDX21 mRNA in an m6A‐dependent manner. DDX21 was highly expressed in AML patients, which indicated a poor survival. Functionally, knockdown of DDX21 inhibited cell proliferation, promoted cell apoptosis and led to cell cycle arrest. Mechanistically, DDX21 recruited transcription factor YBX1 to cooperatively trigger ULK1 expression. Moreover, silencing of ULK1 could reverse the promoting effects of DDX21 overexpression in AML cells.ConclusionsDysregulation of SE‐IGF2BP2/IGF2BP3‐DDX21 axis facilitated the progression of AML. Our findings provide new insights into the link between SEs and m6A modification, elucidate the regulatory mechanisms of IGF2BP2 and IGF2BP3 on DDX21, and reveal the underlying roles of DDX21 in AML.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ddx21 Triggered Ulk1 Expression Via Recruiting Transcription...mentioning

confidence: 96%

See 2 more Smart Citations

m⁶A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia

Zhao,

Zhou,

Qian

et al. 2024

Clinical & Translational Med

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“…Cell death mediated by autophagic machinery, also known as autophagy‐dependent cell death, is an important form of RCD (Su et al, 2021). Autophagy is usually induced by the Adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK), which activates the downstream complex composed making up with unc‐51‐like kinase 1 (ULK1), autophagy related 13 homolog (ATG13), focal adhesion kinase family interacting protein of 200kD (FIP200), and other proteins (Zou et al, 2022). The ULK1 complex activates Beclin 1, an essential protein for the class III phosphoinositide 3 kinase (PI3KC3) complex to induce microtubule‐associated protein 1 light chain 3 (LC3)‐mediated autophagic lysosomal membranes, eventually leading to autophagy (Zhang et al, 2021).…”

Section: Targeting Regulated Cell Death (Rcd) Subroutines With Plant ...mentioning

confidence: 99%

Targeting regulated cell death with plant natural compounds for cancer therapy: A revisited review of apoptosis, autophagy‐dependent cell death, and necroptosis

Yang

Chen

et al. 2023

Phytotherapy Research

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Regulated cell death (RCD) refers to programmed cell death regulated by various protein molecules, such as apoptosis, autophagy‐dependent cell death, and necroptosis. Accumulating evidence has recently revealed that RCD subroutines have several links to many types of human cancer; therefore, targeting RCD with pharmacological small‐molecule compounds would be a promising therapeutic strategy. Moreover, plant natural compounds, small‐molecule compounds synthesized from plant sources, and their derivatives have been widely reported to regulate different RCD subroutines to improve potential cancer therapy. Thus, in this review, we focus on updating the intricate mechanisms of apoptosis, autophagy‐dependent cell death, and necroptosis in cancer. Moreover, we further discuss several representative plant natural compounds and their derivatives that regulate the above‐mentioned three subroutines of RCD, and their potential as candidate small‐molecule drugs for the future cancer treatment.

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A mechanistic insight into the anticancer potentials of resveratrol: Current perspectives

Bhuia,

Chowdhury,

Akter

et al. 2024

Phytotherapy Research

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Resveratrol is a widely recognized polyphenolic phytochemical found in various plants and their fruits, such as peanuts, grapes, and berry fruits. It is renowned for its several health advantages. The phytochemical is well known for its anticancer properties, and a substantial amount of clinical evidence has also established its promise as a chemotherapeutic agent. This study focuses on assessing the anticancer properties of resveratrol and gaining insight into the underlying molecular mechanisms. It also evaluates the biopharmaceutical, toxicological characteristics, and clinical utilization of resveratrol to determine its suitability for further development as a reliable anticancer agent. Therefore, the information about preclinical and clinical studies was collected from different electronic databases up‐to‐date (2018–2023). Findings from this study revealed that resveratrol has potent therapeutic benefits against various cancers involving different molecular mechanisms, such as induction of oxidative stress, cytotoxicity, inhibition of cell migration and invasion, autophagy, arresting of the S phase of the cell cycle, apoptotic, anti‐angiogenic, and antiproliferative effects by regulating different molecular pathways including PI3K/AKT, p38/MAPK/ERK, NGFR‐AMPK‐mTOR, and so on. However, the compound has poor oral bioavailability due to reduced absorption; this limitation is overcome by applying nanotechnology (nanoformulation of resveratrol). Clinical application also showed therapeutic benefits in several types of cancer with no serious adverse effects. We suggest additional extensive studies to further check the efficacy, safety, and long‐term hazards. This could involve a larger number of clinical samples to establish the compound as a reliable drug in the treatment of cancer.

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Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications

Cited by 31 publications

References 349 publications

m⁶A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia

m⁶A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia

Targeting regulated cell death with plant natural compounds for cancer therapy: A revisited review of apoptosis, autophagy‐dependent cell death, and necroptosis

A mechanistic insight into the anticancer potentials of resveratrol: Current perspectives

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Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications

Cited by 31 publications

References 349 publications

m6A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia

m6A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia

Targeting regulated cell death with plant natural compounds for cancer therapy: A revisited review of apoptosis, autophagy‐dependent cell death, and necroptosis

A mechanistic insight into the anticancer potentials of resveratrol: Current perspectives

Contact Info

Product

Resources

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m⁶A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia

m⁶A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia