RAB27B inhibits proliferation and promotes apoptosis of leukemic cells via 3-Hydroxy butyrate dehydrogenase 2 (BDH2)

Meng, Can; Huang, Li; Fu, Xing; Wu, Bin; Lin, Lianbo

doi:10.1080/21655979.2022.2036903

Cited by 7 publications

(4 citation statements)

References 31 publications

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“…We found that RAB27B, but not RAB27A, expression was higher in leukemia cells compared with normal cells (Figure 2F and Supplemental Figure 2A). Importantly, AML patients with high RAB27B expression show reduced survival compared with those with low RAB27B expression in 2 different data sets -UALCAN (http://ualcan.path.uab.edu/) (Figure 2G) and TCGA (https://servers.binf.ku.dk/bloodspot/) (Figure 2H) -consistent with a recent report (29). There was no significant correlation between RAB27A expression and AML patient survival (Supplemental Figure 2, B and C).…”

Section: Resultssupporting

confidence: 89%

RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia

Ren¹,

Xing²,

Lv³

et al. 2023

Journal of Clinical Investigation

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RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2- mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL -deficient or NRAS -mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.

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Section: Resultssupporting

confidence: 89%

RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia

Ren¹,

Xing²,

Lv³

et al. 2023

Journal of Clinical Investigation

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“…Following that, membranes were further incubated with IgG-HRP (MBS435036, 1:1,500, MyBioSource) goat anti-rabbit secondary antibody at 25°C for 2 h. ECL (Thermo Fisher Scientific) was then used to develop signals. Signals were then processed using Image J v1.46 software [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Long noncoding RNA (lncRNA) metallothionein 1 J, pseudogene (MT1JP) is downregulated in triple-negative breast cancer and upregulates microRNA-138 (miR-138) to downregulate hypoxia-inducible factor-1α (HIF-1α)

et al. 2022

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Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer. This study explored the molecular mechanism and influences of metallothionein 1 J, pseudogene (MT1JP), microRNA-138 (miR-138), and hypoxia-inducible factor-1α (HIF-1α) on TNBC cell proliferation and migration. We confirmed TNBC cases by immunohistochemistry (IHC) staining. The expression of MT1JP in two types of tissue collected from 78 TNBC patients was detected by performing real-time quantitative fluorescence PCR (RT-qPCR). To further evaluate the relationship among MT1JP, miR-138 and HIF-1α, expression vectors of MT1JP and HIF-1α, as well as miR-138 mimic and inhibitor, were delivered into BT-549 cells. We observed that MT1JP was downregulated in TNBC. MT1JP was positively correlated with miR-138 but negatively correlated with HIF-1α in TNBC tissues. In TNBC cells, upregulation of miR-138 and downregulation of HIF-1α were observed after overexpression of MT1JP. In addition, overexpression of miR-138 resulted in downregulation of HIF-1α but did not affect the expression of MT1JP. Decreased proliferation rate of TNBC cells was observed after overexpression of MT1JP and miR-138. HIF-1α increased cell proliferation and migration. HIF-1α also suppressed the role of MT1JP and miR-138 in TNBC cell proliferation and migration. In conclusion, our findings demonstrated that MT1JP inhibited TNBC by regulating the miR-138/HIF-1α axis, indicating that MT1JP might serve as a biomarker or target for TNBC treatment.

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“…14 Rab27b, a crucial member of RAB family, has been reported to participate in the invasion and progression of many diverse cancers and relate with poor prognosis. [15][16][17][18][19] Hendrix et al demonstrated that Rab27b can promote the angiogenesis, invasion and metastasis in ER-positive breast cancer, speculating that estrogen may affect the expression of Rab27b. 20 Similarly, as an estrogen-dependent disease, EMS performs tumor-like biological functions such as proliferation and invasiveness.…”

Section: Introductionmentioning

confidence: 99%

“…The RAB family belongs to the small GTPases superfamily which regulates the vesicle trafficking and signal transduction 14 . Rab27b, a crucial member of RAB family, has been reported to participate in the invasion and progression of many diverse cancers and relate with poor prognosis 15–19 . Hendrix et al.…”

Section: Introductionmentioning

confidence: 99%

Rab27b promotes endometriosis by enhancing invasiveness of ESCs and promoting angiogenesis

Shan

Chang

et al. 2023

American J Rep Immunol

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ProblemEndometriosis (EMS) is an estrogen‐dependent disease which is characterized with estrogen‐dependent growth of ectopic endometrium and increased local estrogen production. EMS performs tumor‐like biological functions such as invasiveness and angiogenesis. Rab27b is a member of the Rab family of GTPases, which is strongly associated with the growth, invasion and metastasis of a variety of tumors. However, little is known about the function of Rab27b in EMS. In this study, we intended to investigate the impact of Rab27b and its downstream molecule in the development of EMS.Method of studyNormal endometrium and endometriotic lesions were collected to investigate the expression levels of Rab27b. Then, ESCs were transfected with Rab27b siRNA. We analyzed the influence of Rab27b on the proliferation and invasive activity of ESCs. Conditioned media harvested from Rab27b siRNA‐treated ESCs were used to treat HUVECs. HUVEC Tube formation and ELISA were performed to explored the interactions between ESCs and HUVEC. In addition, ESCs were treated with different concentrations of estrogen. Based on biological database predictions, we explored possible mechanisms through which estrogen regulates the expression of Rab27b.ResultsThe expressions of Rab27b were significantly higher in endometriotic lesions than that in normal endometrium. Rab27b can promote the cell proliferation, migration and invasion of ESCs. The elevated expression of Rab27b, on the one hand, promotes the secretion of MMP9 and increases the invasiveness of ESCs. On the other hand, Rab27b may play a key role in the communication between ESC and endothelial cells, by simulating VEGF secretion and neovascularization. Besides, estrogen upregulated phosphorylated FOXO1 levels in ectopic ESCs, resulting in the promotion of Rab27b expression levels.ConclusionRab27b plays a key role in the development of EMS, which may provide new insights into the pathogenesis of EMS. Our findings may also contribute to the development of therapeutic interventions for EMS.

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RAB27B inhibits proliferation and promotes apoptosis of leukemic cells via 3-Hydroxy butyrate dehydrogenase 2 (BDH2)

Cited by 7 publications

References 31 publications

RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia

RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia

Long noncoding RNA (lncRNA) metallothionein 1 J, pseudogene (MT1JP) is downregulated in triple-negative breast cancer and upregulates microRNA-138 (miR-138) to downregulate hypoxia-inducible factor-1α (HIF-1α)

Rab27b promotes endometriosis by enhancing invasiveness of ESCs and promoting angiogenesis

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