Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

Kadamb, Rama; Leibovitch, Boris A.; Farías, Eduardo; Dahiya, Nisha; Suryawanshi, Hemant; Bansal, Nidhi; Waxman, Samuel

doi:10.1016/j.tranon.2021.101320

Cited by 15 publications

(15 citation statements)

References 62 publications

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“…Our efforts also identified integrin α-6 as another molecule that accumulated on the cell surface when normal LOXL4 was abundantly expressed ( Supplementary Figure S2C ). The heterodimer complex combination of integrin α-6 and integrin β-1has been reported to promote cancer metastatic outgrowth in MDA-MB-231 cells ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2

et al. 2023

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BackgroundLOX family members are reported to play pivotal roles in cancer. Unlike their enzymatic activities in collagen cross-linking, their precise cancer functions are unclear. We revealed that LOXL4 is highly upregulated in breast cancer cells, and we thus sought to define an unidentified role of LOXL4 in breast cancer.MethodsWe established the MDA-MB-231 sublines MDA-MB-231-LOXL4 mutCA and -LOXL4 KO, which stably overexpress mutant LOXL4 that loses its catalytic activity and genetically ablates the intrinsic LOXL4 gene, respectively. In vitro and in vivo evaluations of these cells’ activities of cancer outgrowth were conducted by cell-based assays in cultures and an orthotopic xenograft model, respectively. The new target (s) of LOXL4 were explored by the MS/MS analytic approach.ResultsOur in vitro results revealed that both the overexpression of mutCA and the KO of LOXL4 in cells resulted in a marked reduction of cell growth and invasion. Interestingly, the lowered cellular activities observed in the engineered cells were also reflected in the mouse model. We identified a novel binding partner of LOXL4, i.e., annexin A2. LOXL4 catalyzes cell surface annexin A2 to achieve a cross-linked multimerization of annexin A2, which in turn prevents the internalization of integrin β-1, resulting in the locking of integrin β-1 on the cell surface. These events enhance the promotion of cancer cell outgrowth.ConclusionsLOXL4 has a new role in breast cancer progression that occurs via an interaction with annexin A2 and integrin β-1 on the cell surface.

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Section: Discussionmentioning

confidence: 99%

Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2

et al. 2023

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“…Fibroblasts with high GSL metabolism pathway activity can communicate with smooth muscle cells through PDGFD-PDGFRB interaction, which functions in fibrosis and neovascular formation ( 31 ). Besides, fibroblasts with high GSL metabolism pathway activity can also communicate with keratinocytes through ITGA6-ITGB1 interaction, which play a role to promote cancer cell invasion and metastasis in a variety of cancers, such as cholangiocarcinoma and triple-negative breast cancer ( 32 , 33 ). In addition, the fibroblasts with high GSL metabolism pathway activity can communicate with endothelial cells through the SEMA3B signaling pathway, while SEMA3B is known to be an inhibitor of angiogenesis and cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Revealing the roles of glycosphingolipid metabolism pathway in the development of keloid: a conjoint analysis of single-cell and machine learning

et al. 2023

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Keloid is a pathological scar formed by abnormal wound healing, characterized by the persistence of local inflammation and excessive collagen deposition, where the intensity of inflammation is positively correlated with the size of the scar formation. The pathophysiological mechanisms underlying keloid formation are unclear, and keloid remains a therapeutic challenge in clinical practice. This study is the first to investigate the role of glycosphingolipid (GSL) metabolism pathway in the development of keloid. Single cell sequencing and microarray data were applied to systematically analyze and screen the glycosphingolipid metabolism related genes using differential gene analysis and machine learning algorithms (random forest and support vector machine), and a set of genes, including ARSA,GBA2,SUMF2,GLTP,GALC and HEXB, were finally identified, for which keloid diagnostic model was constructed and immune infiltration profiles were analyzed, demonstrating that this set of genes could serve as a new therapeutic target for keloid. Further unsupervised clustering was performed by using expression profiles of glycosphingolipid metabolism genes to discover keloid subgroups, immune cells, inflammatory factor differences and the main pathways of enrichment between different subgroups were calculated. The single-cell resolution transcriptome landscape concentrated on fibroblasts. By calculating the activity of the GSL metabolism pathway for each fibroblast, we investigated the activity changes of GSL metabolism pathway in fibroblasts using pseudotime trajectory analysis and found that the increased activity of the GSL metabolism pathway was associated with fibroblast differentiation. Subsequent analysis of the cellular communication network revealed the existence of a fibroblast-centered communication regulatory network in keloids and that the activity of the GSL metabolism pathway in fibroblasts has an impact on cellular communication. This contributes to the further understanding of the pathogenesis of keloids. Overall, we provide new insights into the pathophysiological mechanisms of keloids, and our results may provide new ideas for the diagnosis and treatment of keloids.

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“…17 For example, it is reported that specific targeting of SIN3A results in suppression of invasion and metastasis related genes in breast cancer. 18 SIN3A is discovered to be overexpressed in CRC cells and tissues, and SIN3A silencing overtly hampers CRC cell proliferation, migration, and invasion. 19 Since m 6 A modification plays a role in tumors by modulating the biological processes of mRNA, such as stability, translation, and splicing, 5 we accordingly speculate that RBM15-mediated m 6 A modification can affect CRC progression and metastasis via the KLF1/SIN3A axis in an IGF2BP3-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Regulatory mechanism of RNA binding motif protein 15‐mediated N⁶ methyladenosine modification in proliferation, invasion, and migration of colorectal cancer cells

Chen

2023

Environmental Toxicology

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This study aims to explore the regulatory mechanism of RNA binding motif protein 15 (RBM15) on the proliferation, invasion, and migration of colorectal cancer (CRC) cells. RBM15, KLF1, or SIN3A expression in CRC tissues and cells was detected by RT‐qPCR or Western blot. CRC cell functions were measured by CCK‐8, colony formation, and Transwell assays after RBM15 intervention. MeRIP and RIP measured N6 methyladenosine (m6A) and IGF2BP3 enrichment on KLF1 mRNA. ChIP and dual‐luciferase analyzed KLF1 enrichment on SIN3A promoter. Combined experiments verified the effect of KLF1/SIN3A on CRC cell functions. Lung/liver metastasis models were established to validate the effect of RBM15 on CRC in vivo. RBM15, KLF1, and SIN3A were highly expressed in CRC. RBM15 knockdown reduced the proliferation, invasion, and migration of CRC cells in vitro. Mechanistically, RBM15 facilitated KLF1 mRNA stability and expression through IGF2BP3‐dependent m6A modification, thus promoting KLF1 enrichment on the SIN3A promoter and activating SIN3A transcription. Overexpression of KLF1 or SIN3A reversed the inhibitory effect of RBM15 knockdown on CRC cells. In vivo experiments verified that RBM15 promoted tumorigenesis and lung/liver metastasis via KLF1/SIN3A axis. In conclusion, RBM15 stimulated CRC proliferation and metastasis by promoting the KLF1/SIN3A axis through IGF2BP3‐dependent m6A modification.

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Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

Cited by 15 publications

References 62 publications

Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2

Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2

Revealing the roles of glycosphingolipid metabolism pathway in the development of keloid: a conjoint analysis of single-cell and machine learning

Regulatory mechanism of RNA binding motif protein 15‐mediated N⁶ methyladenosine modification in proliferation, invasion, and migration of colorectal cancer cells

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Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

Cited by 15 publications

References 62 publications

Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2

Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2

Revealing the roles of glycosphingolipid metabolism pathway in the development of keloid: a conjoint analysis of single-cell and machine learning

Regulatory mechanism of RNA binding motif protein 15‐mediated N6 methyladenosine modification in proliferation, invasion, and migration of colorectal cancer cells

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Regulatory mechanism of RNA binding motif protein 15‐mediated N⁶ methyladenosine modification in proliferation, invasion, and migration of colorectal cancer cells