BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells

Kim, Namhee; Yoshimaru, Tetsuro; Chen, Yi‐An; Matsuo, Taisuke; Komatsu, Masato; Miyoshi, Yasuo; Tanaka, Eiji; Sasa, Mitsunori; Mizuguchi, Kenji; Katagiri, Toyomasa

doi:10.1371/journal.pone.0127707

Cited by 20 publications

(22 citation statements)

References 27 publications

(62 reference statements)

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“…Moreover, PHB1 is overexpressed in ovarian epithelial tumors and induces cell proliferation 71 , 72 . In estrogen-dependent cancers such as breast cancer, investigators reported that BIG3, a key molecular regulator in the ER signaling pathway, inhibits the nuclear transportation of the PHB2/REA transcription complex, abolishing the inhibitory effect of the PHB2/REA complex on ERα transcriptional activity 73 , 74 . PHB2 was also shown to promote hepatocellular carcinoma growth and malignancy progression in the hypoxic tumor microenvironment 75 .…”

Section: Role Of Phb1 and Phb2 In Tumorigenesismentioning

confidence: 99%

“…As PHB2 is involved in estrogen-dependent cancers such as breast cancer, and BIG3 promotes cancer cell proliferation by inhibiting PHB2 nuclear translocation and promoting the activity of ERα, the BIG3/PHB2 interaction is necessary for tumorigenesis 73 , 74 . Therefore, inhibition of the interaction of BIG3-PHB2 is a feasible strategy in estrogen-dependent cancer therapy.…”

Section: Value Of Phb1 and Phb2 As Therapeutic Targets In Cancer Treamentioning

confidence: 99%

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Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Yang

2018

Cell Death Dis

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Prohibitin (PHB) was originally isolated and characterized as an anti-proliferative gene in rat liver. The evolutionarily conserved PHB gene encodes two human protein isoforms with molecular weights of ~33 kDa, PHB1 and PHB2. PHB1 and PHB2 belong to the prohibitin domain family, and both are widely distributed in different cellular compartments such as the mitochondria, nucleus, and cell membrane. Most studies have confirmed differential expression of PHB1 and PHB2 in cancers compared to corresponding normal tissues. Furthermore, studies verified that PHB1 and PHB2 are involved in the biological processes of tumorigenesis, including cancer cell proliferation, apoptosis, and metastasis. Two small molecule inhibitors, Rocaglamide (RocA) and fluorizoline, derived from medicinal plants, were demonstrated to interact directly with PHB1 and thus inhibit the interaction of PHB with Raf-1, impeding Raf-1/ERK signaling cascades and significantly suppressing cancer cell metastasis. In addition, a short peptide ERAP and a natural product xanthohumol were shown to target PHB2 directly and prohibit cancer progression in estrogen-dependent cancers. As more efficient biomarkers and targets are urgently needed for cancer diagnosis and treatment, here we summarize the functional role of prohibitin domain family proteins, focusing on PHB1 and PHB2 in tumorigenesis and cancer development, with the expectation that targeting the prohibitin domain family will offer more clues for cancer therapy.

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Section: Role Of Phb1 and Phb2 In Tumorigenesismentioning

confidence: 99%

Section: Value Of Phb1 and Phb2 As Therapeutic Targets In Cancer Treamentioning

confidence: 99%

Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Yang

2018

Cell Death Dis

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“…S7 ), it is likely that PHB2 downregulates AQP gene expression. PHB2 translocates to the nucleus with ERα in HeLa and MCF-7 cells and represses ERα-dependent transcription [ 46 , 48 ]. Moreover, ERα up-regulates AQP expression, as mentioned in the Results section [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis

Takashi

Tomita²,

Kuwahara

et al. 2020

Free Radical Biology and Medicine

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Most anti-cancer agents and radiotherapy exert their therapeutic effects via the production of free radicals. Ferroptosis is a recently described cell death process that is accompanied by iron-dependent lipid peroxidation. Hydrogen peroxide (H 2 O 2 ) has been reported to induce cell death. However, it remains controversial whether H 2 O 2 -induced cell death is ferroptosis. In the present study, we aimed to elucidate the involvement of mitochondria in H 2 O 2 -induced ferroptosis and examined the molecules that regulate ferroptosis. We found that one mechanism underlying H 2 O 2 -induced cell death is ferroptosis, which occurs soon after H 2 O 2 treatment (within 3 h after H 2 O 2 treatment). We also investigated the involvement of mitochondria in H 2 O 2 -induced ferroptosis using mitochondrial DNA-depleted ρ 0 cells because ρ 0 cells produce more lipid peroxidation, hydroxyl radicals ( • OH), and are more sensitive to H 2 O 2 treatment. We found that ρ 0 cells contain high Fe 2+ levels that lead to • OH production by H 2 O 2 . Further, we observed that aquaporin (AQP) 3, 5, and 8 bind nicotinamide-adenine dinucleotide phosphate oxidase 2 and regulate the permeability of extracellular H 2 O 2 , thereby contributing to ferroptosis. Additionally, the role of mitochondria in ferroptosis was investigated using mitochondrial transfer in ρ 0 cells. When mitochondria were transferred into ρ 0 cells, the cells exhibited no sensitivity to H 2 O 2 -induced cytotoxicity because of decreased Fe 2+ levels. Moreover, mitochondrial transfer upregulated the mitochondrial quality control protein prohibitin 2 (PHB2), which contributes to reduced AQP expression. Our findings also revealed the involvement of AQP and PHB2 in ferroptosis. Our results indicate that H 2 O 2 treatment enhances AQP expression, Fe 2+ level, and lipid peroxidation, and decrease mitochondrial function by downregulating PHB2, and thus, is a promising modality for effective cancer treatment.

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“…For identification of an O-glycosylation site(s) on ER-α protein, HeLa-GALNT6 stable cells (WT) were transfected with pCAGGSn3FC-ER-α expression vector [18] , [19] and collected after 48 hours of incubation. Cells were lysed with lysis buffer, and Flag-tagged ER-α protein was immunoprecipitated with anti-Flag monoclonal antibody and Protein A/G agarose (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells

et al. 2018

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Alteration of protein O-glycosylation in various human cancers including breast cancer is well known, but molecular roles of their aberrant glycosylations on cancer have not been fully understood. We previously reported critical roles of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6 or GalNAc-T6) that was upregulated in a great majority of breast cancer tissues. Here we further report O-glycosylation of estrogen receptor alpha (ER-α) by GALNT6 and the significant role of its nuclear localization in breast cancer cells. Knockdown of GALNT6 expression in two breast cancer cell lines, T47D and MCF7, in which both ER-α and GALNT6 were highly expressed, by small interfering RNA could significantly attenuate expression of ER-α. Immunocytochemical analysis clearly demonstrated the drastic decrease of ER-α protein in the nucleus of these cancer cells. Accordingly, the downstream genes of the ER-α pathway such as MYC, CCND1, and CTSD were significantly downregulated. We confirmed GALNT6-dependent ER-α O-glycosylation and identified O-glycosylation of S573 in an F domain of ER-α by GALNT6 through LC-MS/MS analysis. We also obtained evidences showing that the glycosylation of ER-α at S573 by GALNT6 is essential for protein stability and nuclear localization of ER-α in breast cancer cells. Furthermore, we designed cell membrane–permeable peptides including the O-glycosylation site and found a significant decrease of the cell viability of breast cancer cells by treatment of these peptides in a GALNT6 expression–dependent manner. Our study suggests that targeting the GALNT6 enzymatic activity as well as the GALNT6/ER-α interaction could be a promising therapeutic approach to ER-α–positive breast cancer patients.

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BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells

Cited by 20 publications

References 27 publications

Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis

Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells

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