Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap

Lee, Youngmin A.; Noon, Luke A.; Akat, Kemal M.; Ybanez, Maria D.; Lee, Ting-Fang; Berres, ML; Fujiwara, Naoto; Goossens, Nicolas; Chou, Hsin I.; Parvin‐Nejad, Fatemeh P.; Khambu, Bilon; Kramer, Elisabeth G.; Gordon, Ronald E.; Pfleger, Cathie M.; Germain, Doris; John, Gareth R.; Campbell, Kirk N.; Yue, Zhenyu; Yin, Xiao Ming; Cuervo, Ana María; Czaja, Mark J.; Fiel, M. Isabel; Hoshida, Yujin; Friedman, Scott L.

doi:10.1038/s41467-018-07338-z

Cited by 117 publications

(141 citation statements)

References 72 publications

(102 reference statements)

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“…Previous studies have demonstrated that loss of hepatic autophagy caused hepatomegaly, liver injury, and fibrosis. (8,10,12,13,26) Although this was consistently observed in the L-ATG5 KO mice, ablation of mTOR in L-ATG5 KO mice markedly attenuated hepatomegaly and liver injury at the early ages of 2 and 6 months, but to a lesser extent in the older mice (9 and 12 months; Fig. 2A-C).…”

Section: Mtor Ablation Attenuates Hepatomegaly Liver Injury and Infmentioning

confidence: 71%

“…The Hippo/YAP signaling pathway is a key regulator of cell proliferation, differentiation, and organ size. Liver injury in L‐ATG7 KO mice is improved by deletion of YAP, which is a coactivator for transcription factor TEA domain transcription factor that may also increase overall protein production similar to NRF2 activation . Therefore, it is likely that the liver pathology in autophagy‐deficient mouse livers could be improved if we can blunt the protein translation or decrease the overall protein production.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic disruption of autophagy in mouse livers, such as the liver-specific deletion of ATG5 or ATG7, leads to hepatomegaly, liver injury, inflammation, fibrosis, and eventual hepatocellular adenoma. (8,(10)(11)(12) Previous studies have demonstrated that the p62-keap1-NRF2 signaling pathway acts as the central player that contributes to the phenotypes of the mice with defective hepatic autophagy. (10,13) Both L-ATG5 or L-ATG7 KO mice have persistent NRF2 activation and deletion of p62 attenuates, but deletion of NRF2 completely eliminates hepatomegaly, liver injury, and liver tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests increased hepatic YAP activation in L-ATG5 KO mice, which is consistent with L-ATG7 KO mice. (12) L-ATG5/mTOR DKO mouse livers had decreased nuclear YAP staining but increased levels of p-YAP and ratio of p-YAP/T-YAP as well as increased MST1, suggesting YAP inactivation ( Fig. 6A-C).…”

Section: Loss Of Mtor Attenuates Atg5-deficiency-induced Yes-associatmentioning

confidence: 96%

“…Indeed, liver-specific autophagy related 7 (L-ATG7) or L-ATG5 knockout (KO) mice exhibit increased liver injury, severe hepatomegaly, inflammation, and fibrosis and eventually develop spontaneous liver tumors. (8)(9)(10)(11)(12) We and others have shown that persistent activation of nuclear factor, erythroid 2 like 2 (NRF2) due to the accumulation of p62/SQSTM1 (hereafter referred to as p62) is the major cause of liver injury and tumorigenesis in autophagy-deficient livers. (10,13) NRF2 is a transcription factor that regulates the expression of important cellular antioxidant genes, drug metabolism enzymes, and transporters, which protect against oxidative and electrophilic stresses.…”

mentioning

confidence: 99%

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Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver

Chao

Yang

et al. 2019

Hepatology

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Autophagy is a lysosomal degradation pathway that degrades cytoplasmic proteins and organelles. Absence of autophagy in hepatocytes has been linked to promoting liver injury and tumorigenesis; however, the mechanisms behind why a lack of autophagy induces these complications are not fully understood. The role of mammalian target of rapamycin (mTOR) in impaired autophagy‐induced liver pathogenesis and tumorigenesis was investigated by using liver‐specific autophagy related 5 knockout (L‐ATG5 KO) mice, L‐ATG5/mTOR, and L‐ATG5/Raptor double knockout (DKO) mice. We found that deletion of mTOR or Raptor in L‐ATG5 KO mice at 2 months of age attenuated hepatomegaly, cell death, and inflammation but not fibrosis. Surprisingly, at 6 months of age, L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice also had increased hepatic inflammation, fibrosis, and liver injury, similar to the L‐ATG5 KO mice. Moreover, more than 50% of L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice already developed spontaneous tumors, but none of the L‐ATG5 KO mice had developed any tumors at 6 months of age. At 9 months of age, all L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO had developed liver tumors. Mechanistically, L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice had decreased levels of hepatic ubiquitinated proteins and persistent nuclear erythroid 2 p45‐related factor 2 activation but had increased Akt activation compared with L‐ATG5 KO mice. Conclusion: Loss of mTOR signaling attenuates the liver pathogenesis in mice with impaired hepatic autophagy but paradoxically promotes tumorigenesis in mice at a relatively young age. Therefore, the balance of mTOR is critical in regulating the liver pathogenesis and tumorigenesis in mice with impaired hepatic autophagy.

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Section: Mtor Ablation Attenuates Hepatomegaly Liver Injury and Infmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Loss Of Mtor Attenuates Atg5-deficiency-induced Yes-associatmentioning

confidence: 96%

mentioning

confidence: 99%

See 3 more Smart Citations

Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver

Chao

Yang

et al. 2019

Hepatology

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The complexity of biological control systems: An autophagy case study

et al. 2022

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Autophagy and YAP1‐WWTR1/TAZ signalling are tightly linked in a complex control system of forward and feedback pathways which determine different cellular outcomes in differing cell types at different time‐points after perturbations. Here we extend our previous experimental and modelling approaches to consider two possibilities. First, we have performed additional mathematical modelling to explore how the autophagy‐YAP1 crosstalk may be controlled by posttranslational modifications of components of the pathways. Second, since analogous contrasting results have also been reported for autophagy as a regulator of other transduction pathways engaged in tumorigenesis (Wnt/β‐catenin, TGF‐β/Smads, NF‐kB or XIAP/cIAPs), we have considered if such discrepancies may be explicable through situations involving competing pathways and feedback loops in different cell types, analogous to the autophagy‐YAP/TAZ situation. Since distinct posttranslational modifications dominate those pathways in distinct cells, these need to be understood to enable appropriate cell type‐specific therapeutic strategies for cancers and other diseases.

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Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma

et al. 2021

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Background Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. Methods We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR‐TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. Results In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR‐TKI‐resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR‐TKI‐resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR‐mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP‐p62 axis, we treated EGFR‐TKI‐resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR‐TKI‐resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD‐L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. Conclusion Finally, we suggest that targeting YAP‐p62 signaling axis can be useful to suppress the EGFR‐TKI‐resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD‐L1 at the same time.

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Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap

Cited by 117 publications

References 72 publications

Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver

Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver

The complexity of biological control systems: An autophagy case study

Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma

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