An Integrative Pan-Cancer Analysis of Kinesin Family Member C1 (KIFC1) in Human Tumors

Wu, Hao; Duan, Yingjuan; Gong, Siming; Zhu, Qiang; Liu, Xuanyou; Liu, Zhenguo

doi:10.3390/biomedicines10030637

Cited by 9 publications

(9 citation statements)

References 65 publications

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“…In the present study, we firstly indicated the tumor‐promoting effects of KIFC1 in PC even in PC cells with DDX6 knockdown, suggesting that the carcinogenesis mediated by DDX6 was achieved probably by upregulation of KIFC1 expression. Wu et al 28 demonstrated that targeting the cell cycle and cell division may be the main mechanisms for the effect of KIFC1 on carcinogenesis. The positive effects of KIFC1 on the cell cycle were also observed in PC cells, and cell proliferation was increased by KIFC1 overexpression.…”

Section: Discussionmentioning

confidence: 99%

The DDX6/KIFC1 signaling axis, as regulated by YY1, contributes to the malignant behavior of pancreatic cancer

Deng,

Liu,

Wang

et al. 2024

The FASEB Journal

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Human DEAD/H box RNA helicase DDX6 acts as an oncogene in several different types of cancer, where it participates in RNA processing. Nevertheless, the role of DDX6 in pancreatic cancer (PC), together with the underlying mechanism, has yet to be fully elucidated. In the present study, compared with adjacent tissues, the level of DDX6 was abnormally increased in human PC tissues, and this increased level of expression was associated with poor prognosis. Furthermore, the role of DDX6 in PC was investigated by overexpressing or silencing the DDX6 in the PC cell lines, SW1990 and PaTu‐8988t. A xenograft model was established by injecting nude mice with either DDX6‐overexpressing or DDX6‐silenced SW1990 cells. DDX6 overexpression promoted the proliferation and cell cycle transition, inhibited the cell apoptosis of PC cells, and accelerated tumor formation, whereas DDX6 knockdown elicited the opposite effects. DDX6 exerted positive effects on PC. RNA immunoprecipitation assay showed that DDX6 bound to kinesin family member C1 (KIFC1) mRNA, which was further confirmed by RNA pull‐down assay. These results suggested that DDX6 positively regulated the expression of KIFC1. KIFC1 overexpression enhanced the proliferative capability of PC cells with DDX6 knockdown and inhibited their apoptosis. By contrast, DDX6 overexpression reversed the inhibitory effect of KIFC1 silencing on tumor proliferation. Subsequently, the transcription factor Yin Yang 1 (YY1) was shown to negatively regulate DDX6 at both the mRNA and protein levels. Dual‐luciferase reporter assay verified that YY1 targeted the promoter of DDX6 and inhibited its transcription. High expression levels of YY1 decreased the proliferation of PC cells and promoted cell apoptosis, although these effects were reversed by DDX6 overexpression. Taken together, YY1 may target the DDX6/KIFC1 axis, thereby negatively regulating its expression, leading to an inhibitory effect on pancreatic tumor.

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Section: Discussionmentioning

confidence: 99%

The DDX6/KIFC1 signaling axis, as regulated by YY1, contributes to the malignant behavior of pancreatic cancer

Deng,

Liu,

Wang

et al. 2024

The FASEB Journal

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“…An integrative pan-cancer study by Wu et al . found that KIFC1 was rarely perturbed at the genetic level in LUAD and other tumor types, suggesting genetic mechanisms are unlikely to account for KIFC1 overexpression[34]. Further studies are needed to decipher the mechanisms driving KIFC1 overexpression but ample evidence indicates that KIFC1 expression is a robust prognostic biomarker in LC.…”

Section: Discussionmentioning

confidence: 99%

“…The recurrence of CA and KIFC1 overexpression in lung tumors, and the dependence of LC with CA on KIFC1 emphasize its therapeutic potential[33, 34]. We propose that KIFC1-targeted therapy could provide a novel strategy for potentiating GIN to lethal levels by forcing LC to divide with multipolar spindles, and that CA and KIFC1 expression could serve as biomarkers to guide effective use.…”

Section: Discussionmentioning

confidence: 99%

Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification

Zhang,

Wu,

et al. 2024

Preprint

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Centrosome amplification (CA), an abnormal increase in the number of centrosomes in the cell, is a recurrent phenomenon in lung and other malignancies. Although CA contributes to tumor development and progression by promoting genomic instability (GIN), it also induces mitotic stress that jeopardizes cellular integrity. The presence of extra centrosomes leads to the formation of multipolar mitotic spindles prone to causing lethal chromosome segregation errors during cell division. To sustain the benefits of CA, malignant cells are dependent on adaptive mechanisms to mitigate its detrimental consequences, and these mechanisms represent therapeutic vulnerabilities. We aimed to discover genetic dependencies associated with CA in lung cancer. Combining a CRISPR/Cas9 functional genomics screen with analyses of tumor genomic data, we identified the motor protein KIFC1 as a putative vulnerability specifically in lung cancers with CA. KIFC1 expression was positively correlated with CA in lung adenocarcinoma (LUAD) cell lines and with a gene expression signature predictive of CA in LUAD tumor tissues. High KIFC1 expression was associated with worse patient outcomes, smoking history, and indicators of GIN. KIFC1 loss-of-function sensitized LUAD cells to potentiation of CA and sensitization was associated with a diminished ability of KIFC1-depleted cells to cluster extra centrosomes into pseudo-bipolar mitotic spindles. Our work suggests that KIFC1 inhibition represents a novel approach for potentiating GIN to lethal levels in LC with CA by forcing cells to divide with multipolar spindles, rationalizing the clinical development of KIFC1 inhibitors and further studies to investigate its therapeutic potential.

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“…We also detected the overexpression of PCLAF, a factor associated with PCNA (also overexpressed in AML), that is associated with DNA synthesis and the G1/S transition (26). On the other hand, we detected several underexpressed genes involved in the regulation of the mitotic spindle and chromosome segregation, namely KIFC1, CENPF, CENPI, ASPM (27)(28)(29)(30)(31)(32). This suggests that the leukemic cells are actively proliferating, but the mechanisms related with the quality of cell division are downregulated, which could trigger genomic irregularities, like aneuploidies, which are a hallmark of cancer.…”

Section: R a F Tmentioning

confidence: 90%

The network structure of hematopoietic cancers

Nakamura-García

Espinal-Enríquez

2022

Preprint

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Hematopoietic cancers (HCs) are a heterogeneous group of malignancies that affect blood, bone marrow and lymphatic system. Despite arising from derivatives of hematopoietic stem cells, each disease has a unique set of characterizing genomic irregularities. Gene co-expression networks (GCNs) have been useful to analyze and integrate information of cancer transcriptomes. Here, we explored the co-expression landscape in HC, by inferring GCNs from four hematopoietic cancers (B and T-cell acute leukemia, -BALL, TALL-, acute myeloid leukemia -AML- and multiple myeloma -MM-) as well as non-cancer bone marrow. We characterized their structure (topological features) and function (enrichment analyses). We found that, as in other types of cancer, the highest co-expression interactions are intra-chromosomal, which is not the case for control GCNs. We also detected a highly co-expressed group of overexpressed pseudogenes in HC networks. The four GCNs present only a small fraction of common interactions, related to canonical functions, like immune response or erythrocyte differentiation. Those genes are differentially expressed in a unique fashion for each HC. For instance, cell cycle-associated genes are underexpressed in MM and AML, slightly overexpressed in BALL but highly overexpressed in TALL. With this approach, we are able to reveal cancer-specific features useful for detection of disease manifestations.

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An Integrative Pan-Cancer Analysis of Kinesin Family Member C1 (KIFC1) in Human Tumors

Cited by 9 publications

References 65 publications

The DDX6/KIFC1 signaling axis, as regulated by YY1, contributes to the malignant behavior of pancreatic cancer

The DDX6/KIFC1 signaling axis, as regulated by YY1, contributes to the malignant behavior of pancreatic cancer

Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification

The network structure of hematopoietic cancers

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