RB1CC1 functions as a tumor-suppressing gene in renal cell carcinoma via suppression of PYK2 activity and disruption of TAZ-mediated PDL1 transcription activation

Chen, Pingfeng; Duan, Youjun; Xin-sheng, LU; Chen, Libo; Zhang, Wang; Wang, Hao; Hu, Rong; Liu, Shimin

doi:10.1007/s00262-021-02913-8

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…This interplay between tumor suppressor genes and gene fusions forms a crucial nexus in malignant transformation, offering novel avenues for research and therapeutic interventions. Within this study, the identified functions of these tumor suppressor genes span a range of cellular processes: they regulate the WNT/β-CATENIN pathway, activate the STING pathway, inhibit epithelial-to-mesenchymal transition, enhance the efficacy of immunotherapy via the PYK2/TAZ/PDL1 pathway, oversee ribosomal RNA maturation, and control tumor growth through the RBMS3/TWIST1/MMP2 pathway [31][32][33][34][35][36][37][38][39][40][41][42][43][44]. These multifaceted roles emphasize the clinical significance of comprehending the molecular mechanisms of these genes.…”

Section: Discussionmentioning

confidence: 99%

“…Within the gene fusions identified in this research, many genes have been linked to tumor-suppressing activities. These include ARHGAP17 [31], CAMTA1 [32,33], DAPK3 [34], FOXO3 [35], HSF2 [36], LEF1 [37], PALMD [38], PNRC1 [39], QKI [40], RB1CC1 [41], RBMS3 [42], RGS2 [43], and ZBTB38 [44]. In a twist of irony, while tumor suppressor genes are designed to combat cancer, their participation in gene fusions can inadvertently promote diseases like HNSCC (head and neck squamous cell carcinoma), cSCC (cutaneous squamous cell carcinoma), and AML (acute myeloid leukemia), as frequently observed in DC cases [45].…”

Section: Genes Engaged In Fusion Events Predominantly Govern Genomic ...mentioning

confidence: 99%

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Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

Güllülü,

Mayer,

Toplek

2024

IJMS

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Dyskeratosis Congenita (DC) is a multisystem disorder intrinsically associated with telomere dysfunction, leading to bone marrow failure (BMF). Although the pathology of DC is largely driven by mutations in telomere-associated genes, the implications of gene fusions, which emerge due to telomere-induced genomic instability, remain unexplored. We meticulously analyzed gene fusions in RNA-Seq data from DC patients to provide deeper insights into DC’s progression. The most significant DC-specific gene fusions were subsequently put through in silico assessments to ascertain biophysical and structural attributes, including charge patterning, inherent disorder, and propensity for self-association. Selected candidates were then analyzed using deep learning-powered structural predictions and molecular dynamics simulations to gauge their potential for forming higher-order oligomers. Our exploration revealed that genes participating in fusion events play crucial roles in upholding genomic stability, facilitating hematopoiesis, and suppressing tumors. Notably, our analysis spotlighted a particularly disordered polyampholyte fusion protein that exhibits robust higher-order oligomerization dynamics. To conclude, this research underscores the potential significance of several high-confidence gene fusions in the progression of BMF in DC, particularly through the dysregulation of genomic stability, hematopoiesis, and tumor suppression. Additionally, we propose that these fusion proteins might hold a detrimental role, specifically in inducing proteotoxicity-driven hematopoietic disruptions.

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Section: Discussionmentioning

confidence: 99%

Section: Genes Engaged In Fusion Events Predominantly Govern Genomic ...mentioning

confidence: 99%

Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

Güllülü,

Mayer,

Toplek

2024

IJMS

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“…Recent studies have showed that RB1CC1 expression deficiency is significantly associated with a worse prognosis in breast cancer [ 61 , 62 ]. Moreover, RB1CC1 has been reported to function as a tumor-suppressing gene in renal cell carcinoma [ 63 ]. RB1CC1-associated signaling sensitizes tumor cells to ferroptosis, which may provide novel therapeutic opportunities for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

METTL14 inhibits malignant progression of oral squamous cell carcinoma by targeting the autophagy-related gene RB1CC1 in an m6A-IGF2BP2-dependent manner

Liang,

Cai,

Hou

et al. 2023

Clinical Science

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N6-methyladenosine (m6A) plays crucial roles in tumorigenesis and autophagy. However, the underlying mechanisms mediated by m6A and autophagy in the malignant progression of oral squamous cell carcinoma (OSCC) remain unclear. In this study, we revealed that downregulated expression of METTL14 was correlated with advanced clinicopathological characteristics and poor prognosis in OSCC. METTL14 knockdown significantly inhibited autophagy and facilitated malignant progression in vitro, and promoted tumor growth and metastasis in vivo. A cell model of rapamycin-induced autophagy was established to identify RB1CC1 as a potential target gene involved in m6A-regulated autophagy in OSCC, through RNA sequencing and methylated RNA immunoprecipitation sequencing (meRIP-seq) analysis. Mechanistically, we confirmed that METTL14 posttranscriptionally enhanced RB1CC1 expression in an m6A-IGF2BP2-dependent manner, thereby affecting autophagy and progression in OSCC, through methylated RNA immunoprecipitation qRT-PCR (meRIP-qPCR), RNA stability assays, mutagenesis assays and dual-luciferase reporter. Collectively, our findings demonstrated that METTL14 serves as an OSCC suppressor by regulating the autophagy-related gene RB1CC1 through m6A modification, which may provide a new insight for the diagnosis and therapy of OSCC.

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“…Rb1-inducible coiled-coil 1 (RB1CC1) is a tumor suppressor that is considered to be a therapeutic target in renal carcinoma [ 98 ]. The overexpression of RB1CC1 decreased the phosphorylation of PyK2 and doxorubicin, which increased RB1CC1 expression and reduced the size of xenografted renal cell carcinoma tumors [ 99 ]. A decrease in PyK2 phosphorylation decreased cancer progression, and cancer migration and invasion were affected by PyK2 and its interactive proteins.…”

Section: Pyk2-associated Molecules In Cancermentioning

confidence: 99%

Activated PyK2 and Its Associated Molecules Transduce Cellular Signaling from the Cancerous Milieu for Cancer Metastasis

Lee

Hong

2022

IJMS

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PyK2 is a member of the proline-rich tyrosine kinase and focal adhesion kinase families and is ubiquitously expressed. PyK2 is mainly activated by stimuli, such as activated Src kinases and intracellular acidic pH. The mechanism of PyK2 activation in cancer cells has been addressed extensively. The up-regulation of PyK2 through overexpression and enhanced phosphorylation is a key feature of tumorigenesis and cancer migration. In this review, we summarized the cancer milieu, including acidification and cancer-associated molecules, such as chemical reagents, interactive proteins, chemokine-related molecules, calcium channels/transporters, and oxidative molecules that affect the fate of PyK2. The inhibition of PyK2 leads to a beneficial strategy to attenuate cancer cell development, including metastasis. Thus, we highlighted the effect of PyK2 on various cancer cell types and the distribution of molecules that affect PyK2 activation. In particular, we underlined the relationship between PyK2 and cancer metastasis and its potential to treat cancer cells.

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RB1CC1 functions as a tumor-suppressing gene in renal cell carcinoma via suppression of PYK2 activity and disruption of TAZ-mediated PDL1 transcription activation

Cited by 8 publications

References 47 publications

Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

METTL14 inhibits malignant progression of oral squamous cell carcinoma by targeting the autophagy-related gene RB1CC1 in an m6A-IGF2BP2-dependent manner

Activated PyK2 and Its Associated Molecules Transduce Cellular Signaling from the Cancerous Milieu for Cancer Metastasis

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