RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling

Tian, Yun; Qin, Lijun; Qiu, Huijuan; Shi, Dingbo; Sun, Rui; Li, Wenbing; Liu, Tianze; Wang, Jingshu; Xu, Tingting; Guo, Wei; Kang, Tiebang; Huang, Wenlin; Wang, Guowen; Deng, Wuguo

doi:10.18632/oncotarget.4868

Cited by 29 publications

(35 citation statements)

References 34 publications

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“…Our finding is further supported by two recent papers from Zhou et al 70. and Tian et al 71. that identified EZH2 and RSP3 as prognostic markers for HNSSC and melanoma, respectively.…”

Section: Discussionsupporting

confidence: 90%

MICU1 drives glycolysis and chemoresistance in ovarian cancer

et al. 2017

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Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca2+ uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.

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“…Our finding is further supported by two recent papers from Zhou et al 70. and Tian et al 71. that identified EZH2 and RSP3 as prognostic markers for HNSSC and melanoma, respectively.…”

Section: Discussionsupporting

confidence: 90%

MICU1 drives glycolysis and chemoresistance in ovarian cancer

et al. 2017

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“…DNA repair may be directly inhibited by occupying substrates like AP sites or indirectly by occupying RECQL4, which acts as positive regulator for early stage base excision repair proteins (14) or nucleotide excision repair proteins like XPA (15). Our results showing increased RECQL4-RPS3 association under conditions of hydrogen peroxide and UV-induced nuclear stress together with reported observations of improved protection against genotoxic stress in RPS3 knockdown cells (27,29) support this model. Our results in U2OS cells indicate that this catalytic collaboration could particularly affect skeletal tissues.…”

Section: Discussionsupporting

confidence: 83%

“…Increased RPS3 expression has been linked with enhanced invasion and migration of GLI2-mediated osteosarcoma cells (28). RPS3 is also overexpressed in melanoma, and its knockdown suppresses cell growth and induces apoptosis in melanoma cells (29).…”

mentioning

confidence: 99%

Ribosomal Protein S3 Negatively Regulates Unwinding Activity of RecQ-like Helicase 4 through Their Physical Interaction

Patil

Hsieh

2017

Journal of Biological Chemistry

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Edited by Patrick SungHuman RecQ-like helicase 4 (RECQL4) plays crucial roles in replication initiation and DNA repair; however, the contextual regulation of its unwinding activity is not fully described. Mutations in RECQL4 have been linked to three diseases including Rothmund-Thomson syndrome, which is characterized by osteoskeletal deformities, photosensitivity, and increased osteosarcoma susceptibility. Understanding regulation of RECQL4 helicase activity by interaction partners will allow deciphering its role as an enzyme and a signaling cofactor in different cellular contexts. We became interested in studying the interaction of RECQL4 with ribosomal protein S3 (RPS3) because previous studies have shown that RPS3 activity is sometimes associated with phenotypes mimicking those of mutated RECQL4. RPS3 is a small ribosomal protein that also has extraribosomal functions, including apurnic-apyrimidinic endonuclease-like activity suggested to be important during DNA repair. Here, we report a functional and physical interaction between RPS3 and RECQL4 and show that this interaction may be enhanced during cellular stress. We show that RPS3 inhibits ATPase, DNA binding, and helicase activities of RECQL4 through their direct interaction. Further domain analysis shows that N-terminal 1-320 amino acids of RECQL4 directly interact with the C-terminal 94 -244 amino acids of RPS3 (C-RPS3). Biochemical analysis of C-RPS3 revealed that it comprises a standalone apurnic-apyrimidinic endonuclease-like domain. We used U2OS cells to show that oxidative stress and UV exposure could enhance the interaction between nuclear RPS3 and RECQL4. Regulation of RECQL4 biochemical activities by RPS3 along with nuclear interaction during UV and oxidative stress may serve to modulate active DNA repair.The RecQ class of helicases function at various stages of DNA metabolism. The presence of at least one homolog in each species evidences their crucial role in maintaining genomic stability. In humans, three of five RecQ helicases have been associated to different genetic disorders. WRN and BLM have been linked with Werner's syndrome and Bloom's syndrome, respectively, and RECQL4 has been linked with Rothmund-Thomson syndrome (RTS), 2 Baller-Gerald syndrome, and RAPADILINO syndrome. Of these, RECQL4 is unique on the basis of its domain structure and function. The N terminus of this protein represents the only human homolog of Saccharomyces cerevisiae essential replication initiation protein Sld2 (1, 2). The helicase domain is conserved across the RecQ class of helicases. Initial reports suggested RECQL4 lacked of helicase activity (3), but annealing, strand exchange and helicase activities of RECQL4 were later demonstrated (4 -7). Human RECQL4 was shown to unwind up to 22-bp double-stranded regions through its helicase activity (6, 7). ATPase and annealing activities of human RECQL4 have also been extensively studied (7,8). Robust helicase and annealing activities on substrates of various lengths have been reported for Drosophila melanogaster R...

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“…CTSD also plays an important role in stress-induced apoptosis in several types of cells [71,72]. Knockdown of RPS3 suppresses cell growth, and induces apoptosis via mitochondrial apoptotic pathway in melanoma cells [73]. Nagao-Kitamoto et al [74] reported that RPS3 knockdown decreases the migration and invasion of osteosarcoma cells, and overexpression of RPS3 promotes the migration and invasion of osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: An iTRAQ-based proteomic analysis

Wenqin

et al. 2016

Life Sciences

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RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling

Cited by 29 publications

References 34 publications

MICU1 drives glycolysis and chemoresistance in ovarian cancer

MICU1 drives glycolysis and chemoresistance in ovarian cancer

Ribosomal Protein S3 Negatively Regulates Unwinding Activity of RecQ-like Helicase 4 through Their Physical Interaction

Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: An iTRAQ-based proteomic analysis

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