The AMP‐dependent kinase pathway is upregulated in <i>BAP1</i> mutant uveal melanoma

Chua, Vivian; Han, Anna; Bechtel, Nelisa; Purwin, Timothy J.; Hunter, Emily; Liao, Connie; Harbour, J. William; Aplin, Andrew E.

doi:10.1111/pcmr.13007

Cited by 14 publications

(16 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, we found that AMPK knockdown by siRNA reduced uveal melanoma cell growth (Appendix Fig S5). This is reminiscent of a previous study showing similar effect of AMPK inhibition in uveal melanoma cells (Chua et al , 2022) and suggesting that AMPK inhibition does not promote uveal cell proliferation.…”

Section: Discussionsupporting

confidence: 83%

LKB1‐SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition

Proteau,

Krossa,

Husser

et al. 2023

EMBO Mol Med

View full text Add to dashboard Cite

Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome‐wide CRISPR‐Cas9 knockout screen, which revealed the LKB1‐SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria‐targeted antioxidant promotes enhanced cell death efficacy in LKB1‐ and SIK2‐negative uveal melanoma cells compared to control cells. Our study also identified an LKB1‐loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.

show abstract

Section: Discussionsupporting

confidence: 83%

LKB1‐SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition

Proteau,

Krossa,

Husser

et al. 2023

EMBO Mol Med

View full text Add to dashboard Cite

show abstract

“…Biallelic inactivation of the tumor-suppressor BAP1 is the distinctive genomic feature of class 2 UM, which occurs through the mutation of one allele and the whole-chromosome loss of the other allele [ 4 ]. While we and others have extensively investigated the downstream effects of BAP1 loss in UM cells [ 5 , 6 , 7 ], the mechanism by which BAP1 loss leads to metastasis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

BAP1 Loss Promotes Suppressive Tumor Immune Microenvironment via Upregulation of PROS1 in Class 2 Uveal Melanomas

Kaler

Dollar

Cruz

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and class 2 UM having a high metastatic risk. Class 2 UM have a distinctive genomic, transcriptomic, histopathologic, and clinical phenotype characterized by biallelic inactivation of the BAP1 tumor-suppressor gene, an immune-suppressive microenvironment enriched for M2-polarized macrophages, and poor response to checkpoint-inhibitor immunotherapy. To identify potential mechanistic links between BAP1 loss and immune suppression in class 2 UM, we performed an integrated analysis of UM samples, as well as genetically engineered UM cell lines and uveal melanocytes (UMC). Using RNA sequencing (RNA-seq), we found that the most highly upregulated gene associated with BAP1 loss across these datasets was PROS1, which encodes a ligand that triggers phosphorylation and activation of the immunosuppressive macrophage receptor MERTK. The inverse association between BAP1 and PROS1 in class 2 UM was confirmed by single-cell RNA-seq, which also revealed that MERTK was upregulated in CD163+ macrophages in class 2 UM. Using ChIP-seq, BAP1 knockdown in UM cells resulted in an accumulation of H3K27ac at the PROS1 locus, suggesting epigenetic regulation of PROS1 by BAP1. Phosphorylation of MERTK in RAW 264.7 monocyte–macrophage cells was increased upon coculture with BAP1−/− UMCs, and this phosphorylation was blocked by depletion of PROS1 in the UMCs. These findings were corroborated by multicolor immunohistochemistry, where class 2/BAP1-mutant UMs demonstrated increased PROS1 expression in tumor cells and increased MERTK phosphorylation in CD163+ macrophages compared with class 1/BAP1-wildtype UMs. Taken together, these findings provide a mechanistic link between BAP1 loss and the suppression of the tumor immune microenvironment in class 2 UMs, and they implicate the PROS1–MERTK pathway as a potential target for immunotherapy in UM.

show abstract

“…127,128 Loss of functional BAP1 is associated with tumorigenesis or BAP1 cancer syndrome, which involves uveal melanoma, mesothelioma, renal cell carcinoma (RCC), HCC, cutaneous melanoma, and breast cancer. [129][130][131] Further, the BAP1 expression has been lower in human lung adenocarcinoma samples than in normal samples and is positively correlated with patient survival. Observations in an animal model of lung adenocarcinoma demonstrated the reduction of BAP1 level during tumor growth that was associated with the reduction of KELCH-ECH-associated protein 1 (Keap-1) expression and increased nuclear factor E2-related factor-2 (Nrf-2, a redox-sensitive transcription factor) activity as well as suppression of oxidative stress.…”

Section: Deubiquitinasesmentioning

confidence: 96%

“…It also affects cell cycle proteins, mitochondrial function, cell survival, tumor metabolism, and immune responses 127,128 . Loss of functional BAP1 is associated with tumorigenesis or BAP1 cancer syndrome, which involves uveal melanoma, mesothelioma, renal cell carcinoma (RCC), HCC, cutaneous melanoma, and breast cancer 129–131 . Further, the BAP1 expression has been lower in human lung adenocarcinoma samples than in normal samples and is positively correlated with patient survival.…”

Section: The Role Of Ups Dysregulation In Tumorigenesismentioning

confidence: 99%

Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

et al. 2023

View full text Add to dashboard Cite

Regarding the multimechanistic nature of cancers, current chemo‐ or radiotherapies often fail to eradicate disease pathology, and frequent relapses or resistance to therapies occur. Brain malignancies, particularly glioblastomas, are difficult‐to‐treat cancers due to their highly malignant and multidimensional biology. Unfortunately, patients suffering from malignant tumors often experience poor prognoses and short survival periods. Thus far, significant efforts have been conducted to discover novel and more effective modalities. To that end, modulation of the ubiquitin‐proteasome system (UPS) has attracted tremendous interest since it affects the homeostasis of proteins critically engaged in various cell functions, for example, cell metabolism, survival, proliferation, and differentiation. With their safe and multimodal actions, phytochemicals are among the promising therapeutic tools capable of turning the operation of various UPS elements. The present review, along with an updated outline of the role of UPS dysregulation in multiple cancers, provided a detailed discussion on the impact of phytochemicals on the UPS function in malignancies, especially brain tumors.

show abstract

The AMP‐dependent kinase pathway is upregulated in BAP1 mutant uveal melanoma

Cited by 14 publications

References 58 publications

LKB1‐SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition

LKB1‐SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition

BAP1 Loss Promotes Suppressive Tumor Immune Microenvironment via Upregulation of PROS1 in Class 2 Uveal Melanomas

Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

Contact Info

Product

Resources

About