Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells

Inami, Yoshihiro; Waguri, Satoshi; Sakamoto, Ayako; Kouno, Tsuguka; Nakada, Kazuto; Hino, Okio; Watanabe, Sumio; Ando, Jin; Iwadate, Manabu; Yamamoto, Masayuki; Lee, Myung-Shik; Tanaka, Keiji; Komatsu, Masaaki

doi:10.1083/jcb.201102031

Cited by 522 publications

(495 citation statements)

References 49 publications

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“…p62 also acts as a cargo receptor for autophagic degradation of ubiquitinated targets (Dikic et al 2010). The results of recent studies revealed that p62 contributes to the accumulation of NRF2 by disrupting the association between NRF2 and KEAP1, which is a negative regulator of NRF2 (Komatsu et al 2010), and that the pathway controlled by NRF2 is activated in p62-positive cases of hepatocellular carcinoma (Inami et al 2011). Therefore, p62 is considered to play an important role in NRF2 stabilization in breast carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, recent data also indicate that p62/SQSTM1 plays an important role in the accumulation of NRF2 in carcinoma cells (Komatsu et al 2010, Inami et al 2011). An association between NRF2 accumulation and adverse clinical outcome of patients has been reported in lung (Solis et al 2010, Inoue et al 2012, gallbladder (Wang et al 2010), and ovarian (Konstantinopoulos et al 2011) carcinomas.…”

Section: Introductionmentioning

confidence: 99%

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NRF2 immunolocalization in human breast cancer patients as a prognostic factor

Onodera¹,

Motohashi²,

Takagi³

et al. 2013

Endocrine-Related Cancer

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Nuclear factor erythroid 2-related factor 2 (NRF2 (NFE2L2)) is an important transcriptional activator involved in the cellular defense mechanisms against electrophilic and oxidative stress. Recent studies have demonstrated that the expression of NRF2 protein is upregulated in several human malignancies and is associated with worse prognosis in these patients. However, the pathological and clinical significance of NRF2 has remained largely unknown in breast cancer patients. Therefore, in this study, we immunolocalized NRF2 in 106 breast carcinoma cases. NRF2 immunoreactivity was mainly detected in the nucleus of the breast carcinoma cells and it was positive in 44% of the cases. NRF2 status was significantly associated with histological grade, Ki-67 labeling index, p62 immunoreactivity, and NAD(P) H:quinone oxidoreductase 1 (NQO1) immunoreactivity, and the results of multivariate analyses revealed that NRF2 status was an independent adverse prognostic factor for both recurrence and disease-free survival of the patients. Subsequent in vitro studies demonstrated that the expression of NRF2 significantly increased the proliferation activity of MCF7 and SK-BR-3 breast carcinoma cells. These results indicate that nuclear NRF2 protein plays important roles in the proliferation and/or progression of breast carcinoma, and nuclear NRF2 immunoreactivity is therefore considered a potent prognostic factor in breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

Onodera¹,

Motohashi²,

Takagi³

et al. 2013

Endocrine-Related Cancer

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“…Because of this, we propose a role for SQSTM1 in LTC oncogenesis. SQSTM1 accumulation in aggregates is commonly observed in human tumors such as hepatocellular carcinoma and malignant glioma (104)(105)(106)(107). Furthermore, the Ser-351 phosphorylation of SQSTM1 was found to have a crucial role in this Nrf2 activation and the growth of tumor cells (9).…”

Section: Fig 11mentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

Gjyshi

Flaherty

Veettil

et al. 2015

J Virol

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Nuclear factor erythroid 2-related factor 2 (Nrf2), the cellular master regulator of the antioxidant response, dissociates from its inhibitor Keap1 when activated by stress signals and participates in the pathogenesis of viral infections and tumorigenesis. Early during de novo infection of endothelial cells, KSHV induces Nrf2 through an intricate mechanism involving reactive oxygen species (ROS) and prostaglandin E2 (PGE2). When we investigated the Nrf2 activity during latent KSHV infection, we observed increased nuclear serine-40-phosphorylated Nrf2 in human KS lesions compared to that in healthy tissues. Using KSHV long-term-infected endothelial cells (LTC) as a cellular model for KS, we demonstrated that KSHV infection induces Nrf2 constitutively by extending its half-life, increasing its phosphorylation by protein kinase C (PKC) via the infection-induced cyclooxygenase-2 (COX-2)/PGE2 axis and inducing its nuclear localization. Nrf2 knockdown in LTC decreased expression of antioxidant genes and genes involved in KS pathogenesis such as the NAD(P)H quinone oxidase 1 (NQO1), gamma glutamylcysteine synthase heavy unit (␥GCSH), the cysteine transporter (xCT), interleukin 6 (IL-6), and vascular endothelial growth factor A (VEGF-A) genes. Nrf2 activation was independent of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1; p62). SQSTM1 levels were elevated in LTC, a consequence of protein accumulation due to decreased autophagy and Nrf2-mediated transcriptional activation. SQSTM1 was phosphorylated on serine-351 and -403, while Keap1 was polyubiquitinated with lysine-63-ubiquitin chains, modifications known to increase their mutual affinity and interaction, leading to Keap1 degradation and Nrf2 activation. The latent KSHV protein Fas-associated death domain-like interleukin-1␤-converting enzyme-inhibitory protein (vFLIP) increased SQSTM1 expression and activated Nrf2. Collectively, these results demonstrate that KSHV induces SQSTM1 to constitutively activate Nrf2, which is involved in the regulation of genes participating in KSHV oncogenesis. IMPORTANCEThe transcription factor Nrf2 is activated by stress signals, including viral infection, and responds by activating the transcription of cytoprotective genes. Recently, Nrf2 has been implicated in oncogenesis and was shown to be activated during de novo KSHV infection of endothelial cells through ROS-dependent pathways. The present study was undertaken to determine the mechanism of Nrf2 activation during prolonged latent infection of endothelial cells, using an endothelial cell line latently infected with KSHV. We show that Nrf2 activation was elevated in KSHV latently infected endothelial cells independently of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1), which was involved in the degradation of the Nrf2 inhibitor Keap1. Furthermore, our results indicated that the KSHV latent protein vFLIP participates in Nrf2 activation. This study suggests that KSHV hijacks the host's autophagic protein SQS...

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“…[6][7][8] In cancer, autophagy is thought to act as a tumor suppressor mechanism during tumor initiation by contributing to the maintenance of genomic integrity and the elimination of procarcinogens. [9][10][11] Accordingly, genetic alterations on autophagic genes, such as BECN1 and ATG7, have been associated with a higher tumor incidence and resistance to therapies; 9,12,13 several tumor suppressor genes also induce autophagy, such as PTEN, TSC1/2, and STK11/LKB1. 14 However, in established solid tumors, autophagy may contribute to tumor adaptation and survival during metabolic stress in addition to favoring cell resistance to therapy.…”

Section: Introductionmentioning

confidence: 99%

Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage

et al. 2015

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Abbreviations: 3MA, 3-methyladenine; AO, acridine orange; BafA1, bafilomycin A 1 ; CDKN1A/p21, cyclin-dependent kinase inhibitor 1A (p21, Cip1); cP1-4, cellular population 1 to 4; CPD, cumulative population doubling; DDR, DNA damage response; DFM, drug-free medium; H2AFX, H2A histone family, member X; MAP1LC3A/LC3, microtubule-associated protein 1 light chain 3 a; MTOR, mechanistic target of rapamycin; MTORC1, MTOR complex 1; NA, nuclear area; NMA, nuclear morphometric analysis; nP1-5, nuclear population 1 to 5; PRKAA/AMPKa, protein kinase, AMP-activated; RAPA, rapamycin; RPTOR/RAPTOR, regulatory-associated protein of MTOR, complex 1; SA-b-gal, senescence associated b-galactosidase assay; SQSTM1/p62, sequestosome 1; TMZ, temozolomide.Autophagy and senescence have been described as central features of cell biology, but the interplay between these mechanisms remains obscure. Using a therapeutically relevant model of DNA damage-induced senescence in human glioma cells, we demonstrated that acute treatment with temozolomide induces DNA damage, a transitory activation of PRKAA/AMPK-ULK1 and MAPK14/p38 and the sustained inhibition of AKT-MTOR. This produced a transient induction of autophagy, which was followed by senescence. However, at the single cell level, this coordinated transition was not observed, and autophagy and senescence were triggered in a very heterogeneous manner. Indeed, at a population level, autophagy was highly negatively correlated with senescence markers, while in single cells this correlation did not exist. The inhibition of autophagy triggered apoptosis and decreased senescence, while its activation increased temozolomide-induced senescence, showing that DNA damage-induced autophagy acts by suppressing apoptosis.

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Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells

Abstract: Impaired autophagy stabilizes p62 and promotes tumorigenesis through activation of the Nrf2 transcription factor.

Cited by 522 publications

References 49 publications

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage

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