c-Myc and E2F1 drive PBK/TOPK expression in high-grade malignant lymphomas

Hu, Fang; Gartenhaus, Ronald B.; Zhao, Xianfeng; Fang, Hong-Bin; Minkove, S.; Poss, Daniella E.; Rapoport, Aaron P.

doi:10.1016/j.leukres.2012.11.010

Cited by 42 publications

(28 citation statements)

References 42 publications

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“…Multiple studies have found that PBK overexpresses in breast, prostate, colon, bladder, and lung cancers and is a prognostic biomarker for poor outcomes [2-5]. Previous studies have shown that expression of PBK is regulated by Myc and E2F1 transcriptional factors [34]. Immunofluorescent staining in Figure 3B has shown that PBK is localized in nuclei, confirming that PBK is a nuclear kinase and functions in phosphorylation of nuclear proteins.…”

Section: Discussionmentioning

confidence: 54%

PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation

et al. 2015

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PDZ binding-kinase (PBK) (also named T-lymphokine-activated killer cell-originated protein kinase (TOPK)), a serine/threonine kinase, is tightly controlled in normal tissues but elevated in many tumors, and functions in tumorigenesis and metastasis. However, the signaling that regulates expression of PBK in cancer cells remains elusive. Here we show that atorvastatin (Lipitor), an inhibitor of hydroxymethylglutaryl co-enzyme A (HMG-CoA) reductase that is a rate-limiting enzyme of mevalonate pathway, down-regulates expression of PBK by impairing protein geranylgeranylation. The shRNA knockdown demonstrated that Yes-associated protein (YAP) mediates geranylgeranylation-regulated expression of PBK. Importantly, atorvastatin or the geranylgeranyltransferase I inhibitor GGTI-298 inhibited breast cancer cell proliferation through inactivation of YAP signaling and down-regulation of PBK. These findings have defined a new signaling pathway that regulated expression of PBK and identified PBK as a downstream target of the Hippo-YAP signaling, uncoverd a mechanism underlying the anti-cancer effect by inhibition of mevalonate pathway and geranylgeranylation, and provided a potential target for breast cancer targeted therapy.

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Section: Discussionmentioning

confidence: 54%

PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation

et al. 2015

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“…TOPK is not detected in normal tissues except for the germ cells of testis and several fetal tissues, including neural stem and progenitor cells . However, TOPK is overexpressed in various types of cancers, including lung cancer, lymphoma, leukemia, breast cancer and colorectal cancers . Recent studies have shown that TOPK plays a global mitotic role by simultaneously regulating hundreds of DNA binding proteins .…”

Section: Introductionmentioning

confidence: 99%

“…5,[7][8][9] However, TOPK is overexpressed in various types of cancers, including lung cancer, lymphoma, leukemia, breast cancer and colorectal cancers. [9][10][11][12][13] Recent studies have shown that TOPK plays a global mitotic role by simultaneously regulating hundreds of DNA binding proteins. 14 Knockdown of TOPK leads to mitotic failures in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Impact of a novel biomarker, T‐LAK cell‐originating protein kinase (TOPK) expression on outcome in malignant glioma

et al. 2017

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This study aimed to evaluate the biological features of T-lymphokine-activated killer cell-originating protein kinase (TOPK) in vitro and to assess clinical impact of TOPK on the outcome in patients with malignant glioma. TOPK protein level and TOPK mRNA and protein levels in six glioma cell lines were examined using Western blot and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Immunohistochemistry was performed to examine their subcellular localization of TOPK. Using surgical specimens from 57 patients with gliomas, TOPK and Ki-67 expressions were examined by immunohistochemistry. Their co-localization was also examined with double immunofluorescence immunohistochemistry. Impacts of TOPK/Ki-67 expression on the overall survival (OS) and progression-free survival (PFS) in 32 patients with glioblastoma multiforme (GBM) were examined, using Kaplan-Meier and Cox proportion hazard models. Immunohistochemistry revealed that approximately 20-30% of glioma cells were positive for TOPK in vitro. TOPK mRNA was identified in all glioma cell lines on RT-PCR. The value of TOPK/GAPDH was 0.27 ± 0.11. TOPK and Ki-67 expressions were significantly higher in GBM patients than in non-GBM patients. A majority of TOPK-positive cells were also positive for Ki-67 and vice versa. Multivariate analysis revealed that a low TOPK expression (≤ 12.7%) was an independent predictor of longer OS (P = 0.0372), and that gross total removal and a low TOPK expression (≤ 12.7%) were independent predictors of longer PFS (P = 0.0470 and P = 0.0189, respectively). The findings strongly suggest biological and clinical importance of TOPK expression in gliomas, indicating a novel therapeutic potential of TOPK inhibitors to treat malignant gliomas.

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“…(40) Interestingly, PBK is overexpressed in lymphomas and it was recently discovered that MYC positively regulates PBK expression by binding to its promoter. (41) We observed that MYCN and PBK expression are strongly correlated in neuroblastoma tumors ( Supplementary Fig. S4B-C).…”

Section: Two Neuroblastoma Oncogenes Lin28b and Mycn Regulate The Ementioning

confidence: 69%

LIN28B-PDZ Binding Kinase Signaling Promotes Neuroblastoma Metastasis

Chen

Cox

Annam

et al. 2019

Preprint

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Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis. We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype. Our studies reveal that the let-7 family, which LIN28B inhibits, opposes the effects of LIN28B. Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target. PBK is a serine/threonine kinase that promotes the proliferation and selfrenewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies. We demonstrate that PBK is both a novel direct target of let-7 and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK. Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B.Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.3

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c-Myc and E2F1 drive PBK/TOPK expression in high-grade malignant lymphomas

Cited by 42 publications

References 42 publications

PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation

PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation

Impact of a novel biomarker, T‐LAK cell‐originating protein kinase (TOPK) expression on outcome in malignant glioma

LIN28B-PDZ Binding Kinase Signaling Promotes Neuroblastoma Metastasis

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