Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses

Torrente, Laura; Sánchez, Carlos; Moreno, Rita; Chowdhry, Sudhir; Cabello, Pablo; Isono, Kyoichi; Koseki, Haruhiko; Honda, Tadashi; Hayes, John D.; Dinkova‐Kostova, Albena T.; Vega, Laureano de la

doi:10.1038/onc.2017.221

Cited by 80 publications

(63 citation statements)

References 73 publications

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“…Besides, HIPK2 is required for robust NRF2 responsiveness in cancer cells and in vivo. 58 HIPK2 also controls the levels of Notch1, a well-established factor with dual roles in cancer, that can act as both tumour suppressor and oncogenic factor, depending on the context. 59,60 These reports add strength to the notion that HIPK2 possesses context-dependent roles in cancer.…”

Section: Discussionmentioning

confidence: 99%

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Homeodomain‐interacting protein kinase 2 suppresses proliferation and aerobic glycolysis via ERK/cMyc axis in pancreatic cancer

Qin

et al. 2019

Cell Proliferation

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Objectives To investigate the roles of the homeodomain‐interacting protein kinase (HIPK) family of proteins in pancreatic cancer prognosis and the possible molecular mechanism. Materials and Methods The expression of HIPK family genes and their roles in pancreatic cancer prognosis were analysed by using The Cancer Genome Atlas (TCGA). The roles of HIPK2 in pancreatic cancer proliferation and glycolysis were tested by overexpression of HIPK2 in pancreatic cancer cells, followed by cell proliferation assay, glucose uptake analysis and Seahorse extracellular flux analysis. The mechanism of action of HIPK2 in pancreatic cancer proliferation and glycolysis was explored by examining its effect on the ERK/cMyc axis. Results Decreased HIPK2 expression indicated worse prognosis of pancreatic cancer. Overexpression of HIPK2 in pancreatic cancer cells decreased cell proliferation and attenuated aerobic glycolysis, which sustained proliferation of cancer cells. HIPK2 decreased cMyc protein levels and expression of cMyc‐targeted glycolytic genes. cMyc was a mediator that regulated HIPK2‐induced decrease in aerobic glycolysis. HIPK2 regulated cMyc protein stability via ERK activation, which phosphorylated and controlled cMyc protein stability. Conclusions HIPK2 suppressed proliferation of pancreatic cancer in part through inhibiting the ERK/cMyc axis and related aerobic glycolysis.

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Section: Discussionmentioning

confidence: 99%

“… 56,57. Besides, HIPK2 is required for robust NRF2 responsiveness in cancer cells and in vivo 58. For example, HIPK2 is a downstream target of NRF2 (nuclear factor, erythroid 2 like 2), which is an important regulator of intracellular redox homeostasis and oncogenes in cancer.…”

mentioning

confidence: 99%

Homeodomain‐interacting protein kinase 2 suppresses proliferation and aerobic glycolysis via ERK/cMyc axis in pancreatic cancer

Qin

et al. 2019

Cell Proliferation

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“…Indeed, HIPK2 is a well-characterized p53 regulator, promoting the expression of apoptosis-related p53-target genes [82]. Recently, it has demonstrated that HIPK2 ablation induces cerebellar dysfunction compatible with an ataxic-like phenotype [83] and, being a redox-sensitive kinase [84] Nrf2, which positively regulates its expression. HIPK2, in turn, supports Nrf2 cytoprotective activity, promoting its nuclear accumulation and activity [84].…”

Section: Nrf2 Cross-talks With Other Cellular Pathwaysmentioning

confidence: 99%

“…Recently, it has demonstrated that HIPK2 ablation induces cerebellar dysfunction compatible with an ataxic-like phenotype [83] and, being a redox-sensitive kinase [84] Nrf2, which positively regulates its expression. HIPK2, in turn, supports Nrf2 cytoprotective activity, promoting its nuclear accumulation and activity [84]. These data suggest that HIPK2 may be an important modulator of Nrf2 in the regulation of oxidative stress-related genes and correlated diseases.…”

Section: Nrf2 Cross-talks With Other Cellular Pathwaysmentioning

confidence: 99%

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

Paladino

Conte

Caggiano

et al. 2018

Cell Physiol Biochem

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A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.

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“…The cell lines were validated by STR profiling and were routinely tested to ensure that they were mycoplasma-negative. CRISPR-edited NRF2-knockout (NRF2-KO) and NRF2-gain-of-function (NRF2-GOF) DLD1 cell lines were produced as previously described [22].…”

Section: Cell Culturementioning

confidence: 99%

The kinase inhibitor AT9283 selectively kills colorectal cancer cells with hyperactive NRF2

Torrente

Casares

et al. 2019

Preprint

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Short title: Synthetic lethality between hyperactive NRF2 and AT9283Keywords: NRF2/ AT9283/ Synthetic Lethality/ Colorectal cancer Highlights:-We present a new model for NRF2 hyperactivation in colorectal cancer cells.-AT9283 selectively kills cancer cells with hyperactive NRF2 -Both genetic and pharmacological activation of NRF2 sensitise cells to AT9283 ABSTRACT Aberrant hyperactivation of NRF2 is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis. The identification of ways to overcome the protection provided by NRF2 and selectively kill cancer cells addicted to NRF2 is a desirable goal. Exploiting the CRISPR/Cas9 technology, we generated colorectal cancer cell lines with hyperactive NRF2, and used them to perform a drug screen. We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation. Our results show that hyperactivation of NRF2 presents a potential vulnerability that could be therapeutically exploited, and further suggest that AT9283, a drug that is currently in clinical trials, holds promise for the treatment of tumours with hyperactive NRF2.

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Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses

Cited by 80 publications

References 73 publications

Homeodomain‐interacting protein kinase 2 suppresses proliferation and aerobic glycolysis via ERK/cMyc axis in pancreatic cancer

Homeodomain‐interacting protein kinase 2 suppresses proliferation and aerobic glycolysis via ERK/cMyc axis in pancreatic cancer

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

The kinase inhibitor AT9283 selectively kills colorectal cancer cells with hyperactive NRF2

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