The INPP4B paradox: Like PTEN, but different

Hamila, Sabryn A.; Ooms, Lisa M; Rodgers, Samuel J.; Mitchell, Christina A.

doi:10.1016/j.jbior.2021.100817

Cited by 11 publications

(10 citation statements)

References 176 publications

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“…The advances achieved recently shed new light on the pivotal role of inositol polyphosphate 4-phosphatase type II (INPP4B)-mediated signaling in the regulation of cancer survival, motility, and invasiveness ( 6 ). The human INPP4B gene is located on chromosome 4q31.21 and encodes inositol polyphosphate 4-phosphatase II, which is widely expressed in many human tissues, with the highest expression in the skeletal muscle and heart and relatively low expression in the brain ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma

Chen

Gao

et al. 2022

Front. Oncol.

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Inositol polyphosphate-4-phosphatase type II (INPP4B) has been identified as a tumor suppressor, while little is known about its expression and function in multiple myeloma (MM). In this study, we evaluated the expression of INPP4B in 28 cases of newly diagnosed MM patients and 42 cases of extramedullary plasmacytoma (EMP) patients compared with normal plasma cells and found that low INPP4B expression was correlated with poor outcomes in MM patients. Moreover, expression of INPP4B in seven MM cell lines was all lower than that in normal plasma cells. In addition, loss of function of INPP4B promoted cell proliferation in MM cells; however, gain of function suppressed MM cells proliferation and arrested the cell cycle at G0/G1 phage. Meanwhile, knockdown of INPP4B enhanced resistance, but overexpression promoted sensitivity to bortezomib treatment in MM cells. Mechanistically, we found that INPP4B exerted its role via inhibiting the phosphorylation of Akt at lysine 473 but not threonine 308, which attenuated the activation of the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Therefore, we identified an inhibitory effect of INPP4B in MM, and our findings suggested that loss of INPP4B expression is a risk factor of aggressive MM.

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Section: Introductionmentioning

confidence: 99%

Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma

Chen

Gao

et al. 2022

Front. Oncol.

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“…INPP4B is a lipid phosphatase known to regulate phosphoinositide 3-kinase (PI3K)/AKT signaling. Originally, INPP4B was described as a tumor suppressor gene in various cancers, but it is now controversially discussed as an oncogenic driver (for review see: [ 11 , 17 ]). However, increased INPP4B expression has been reported for several tumor entities, e.g., AML, melanoma, and colon cancers, suggesting the oncogenic potential of INPP4B (for review see: [ 17 ]).…”

Section: Discussionmentioning

confidence: 99%

“…INPP4B has been reported as a negative regulator of the phosphatidylinositol kinase 3 (PI3K)/AKT signaling pathway [12,13]. PI3K and phosphatidylinositol phosphate kinase 4 (PIP4K) phosphorylate phosphatidylinositol-3 (PI(3)P) and -4 phosphate (PI(4)P), which subsequently phosphorylate and thereby activate AKT, a potent driver of tumorigenic cell growth, which promotes cell proliferation, survival, and migration ( [11,[14][15][16] for review see: [17]). Phosphorylated AKT in turn activates the signal transduction of other downstream molecules in the PI3K/AKT signaling pathway [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…As INPP4B levels are signifcantly decreased in various cancers, it has frst been described as a tumor suppressor gene, e.g., in prostate, basallike breast, ovarian, cervical, gallbladder, and gastric cancer [21,[24][25][26][27][28][29], as well as thyroid neoplasm [30] and multiple myeloma [31]. However, several studies have reported an increased INPP4B expression, e.g., in AML, colon cancer, and a subset of melanomas [32][33][34] revealing the paradoxical role of an oncogene [17,35].…”

Section: Introductionmentioning

confidence: 99%

“…The tumor suppressive function of INPP4B is most likely attributable to the negative regulation of PI3K/AKT signaling, whereas its oncogenic function is still unclear, and promotion of SGK3 signaling, inhibition of phosphatase and tensin homolog (PTEN)- dependent AKT activation, and enhancement of DNA repair mechanisms to confer chemoresistance have been proposed as potential mechanisms [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma

Miroschnikov

Dräger

Meenen

et al. 2023

Journal of Oncology

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The chemotherapy of retinoblastoma (RB), a malignant ocular childhood disease, is often limited by the development of resistance against commonly used drugs. We identified inositol polyphosphate 4-phosphatase type II (INPP4B) as a differentially regulated gene in etoposide-resistant RB cell lines, potentially involved in the development of RB resistances. INPP4B is controversially discussed as a tumor suppressor and an oncogenic driver in various cancers, but its role in retinoblastoma in general and chemoresistant RB in particular is yet unknown. In the study presented, we investigated the expression of INPP4B in RB cell lines and patients and analyzed the effect of INPP4B overexpression on etoposide resistant RB cell growth in vitro and in vivo. INPP4B mRNA levels were significantly downregulated in RB cells lines compared to the healthy human retina, with even lower expression levels in etoposide-resistant compared to the sensitive cell lines. Besides, a significant increase in INPP4B expression was observed in chemotherapy-treated RB tumor patient samples compared to untreated tumors. INPP4B overexpression in etoposide-resistant RB cells resulted in a significant reduction in cell viability with reduced growth, proliferation, anchorage-independent growth, and in ovo tumor formation. Caspase-3/7-mediated apoptosis was concomitantly increased, suggesting a tumor suppressive role of INPP4B in chemoresistant RB cells. No changes in AKT signaling were discernible, but p-SGK3 levels increased following INPP4B overexpression, indicating a potential regulation of SGK3 signaling in etoposide-resistant RB cells. RNAseq analysis of INPP4B overexpressing, etoposide-resistant RB cell lines revealed differentially regulated genes involved in cancer progression, mirroring observed in vitro and in vivo effects of INPP4B overexpression and strengthening INPP4B’s importance for cell growth control and tumorigenicity.

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A meta‐analysis and polygenic score study identifies novel genetic markers for waist‐hip ratio in African populations

Zhong,

Onyenobi,

Duomatey

et al. 2024

Obesity

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ObjectiveUnderstanding the genetic underpinnings of anthropometric traits in diverse populations is crucial for gaining insights into their biological mechanisms and potential implications for health.MethodsWe conducted a genome‐wide association study, meta‐analysis, and gene set analysis of waist‐hip ratio (WHR), WHR adjusted for BMI (WHRadjBMI), waist circumference, BMI, and height using the African Collaborative Center for Microbiome and Genomics Research (ACCME) cohort (n = ~11,000) for discovery and polygenic score target analyses and the Africa America Diabetes Mellitus (AADM) study (n = ~5200) for replication and polygenic score validation. We generated and compared polygenic scores from European, African, Afro‐Caribbean, and multiethnic ancestry populations.ResultsThe top loci associated with each trait in the meta‐analysis were in CD36 (rs3211826 [p = 5.90 × 10−12] for WHR and rs73709003 [p = 1.75 × 10−13] for WHRadjBMI), IFI27L1 (rs59775050 [p = 2.66 × 10−08] for waist circumference), INPP4B (rs2636629 [p = 1.44 × 10−09] for BMI), and HMGA1 (rs6937622 [p = 1.40 × 10−15] for height) gene regions. A novel variant rs7797157, near GNAT3, was also significantly associated with WHR (p = 2.50 × 10−10) and WHRadjBMI (p = 2.66 × 10−11). The ancestry‐specific parameters for the best predictive polygenic scores were European ancestry (R2 = 0.68%; p = 1.63 × 10−16) and multiethnic ancestry (R2 = 0.06%; p = 1.29 × 10−02) for WHR; European ancestry (R2 = 1.36%; p = 2.94 × 10−31) and multiethnic ancestry (R2 = 1.12%; p = 3.52 × 10−25) for BMI; and European ancestry (R2 = 3.16%; p = 2.95 × 10−73), African ancestry (R2 = 4.16%; p = 1.75 × 10−96), and African and Afro‐Caribbean ancestry (R2 = 2.67%; p = 4.35 × 10−62) for height.ConclusionsThe discovery of a novel locus for WHR and genetic signals for each trait and the assessment of polygenic score performance underscore the importance of conducting well‐powered studies in diverse populations.

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The INPP4B paradox: Like PTEN, but different

Cited by 11 publications

References 176 publications

Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma

Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma

Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma

A meta‐analysis and polygenic score study identifies novel genetic markers for waist‐hip ratio in African populations

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