GASC1 promotes hepatocellular carcinoma progression by inhibiting the degradation of ROCK2

Shao, Na; Cheng, Jiamin; Huang, Hong; Gong, Xiaoshan; Lu, Yong; Idris, Muhammad; Xu, Peng; Ong, Belinda X.; Zhang, Qiongyi; Xu, Feng; Liu, Chungang

doi:10.1038/s41419-021-03550-w

Cited by 8 publications

(4 citation statements)

References 60 publications

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“…However, few studies have explored the functions of KDM4C in HCC. Our results demonstrate that KDM4C is upregulated in HCC cells and drives cell growth and proliferation in vitro and in vivo, which is consistent with a recent study showing that KDM4C knockdown led to decreased HCC proliferation by stabilizing ROCK2 [ 29 ]. In addition, we confirmed for the first time that KDM4C is inversely correlated with the migration of HCC cells.…”

Section: Discussionsupporting

confidence: 92%

KDM4C silencing inhibits cell migration and enhances radiosensitivity by inducing CXCL2 transcription in hepatocellular carcinoma

Zeng

Xue

et al. 2023

Cell Death Discov.

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KDM4C, which is a histone lysine demethylase, has been proposed to participate in the malignant transformation and progression of several types of cancer. However, its roles in hepatocellular carcinoma (HCC) remain poorly understood. Here, we find that KDM4C protein expression is increased in HCC and promotes HCC cell growth, proliferation and migration. Furthermore, we provide evidence that depletion of KDM4C leads to a defective G2/M checkpoint, increases radiation-induced DNA damage, impairs DNA repair and enhances radiosensitivity in HCC cells. Using RNA sequencing, we identify that the chemokine CXCL2 is a downstream effector of KDM4C. KDM4C knockdown increases the binding of H3K36me3 to the promoter of CXCL2, thus upregulating CXCL2 expression and promoting CXCL2 secretion in HCC cells. Importantly, the observed effects of KDM4C depletion in HCC cells can be partially rescued by CXCL2 silencing. Thus, our findings reveal that KDM4C is involved in cell migration and radiosensitivity by modulating CXCL2 transcription, indicating that KDM4C may be a potential therapeutic target in HCC.

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Section: Discussionsupporting

confidence: 92%

KDM4C silencing inhibits cell migration and enhances radiosensitivity by inducing CXCL2 transcription in hepatocellular carcinoma

Zeng

Xue

et al. 2023

Cell Death Discov.

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“…The association of some mutations in these cancer genes with CD13 expression has been reported. Overexpression of KDM4C was observed in CD13-positive LCSCs [ 107 ]. Its depletion decreased tumor initiation, as examined by sphere formation and xenograft assays.…”

Section: Resultsmentioning

confidence: 99%

Genetic heterogeneity of liver cancer stem cells

Kim

et al. 2022

Anat Cell Biol

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Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer.Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.

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“…Most recently, KDM4C has been described as a regulator of stemness [ 26 – 29 ], cancer cell resistance [ 30 , 31 ] and cancer progression [ 32 , 33 ] in various cancer models and KDM4C germline variants may increase multi-cancer vulnerability through dysregulation of target histone methylation [ 34 ]. In murine models of acute myeloid leukemia (AML) driven by MLL-rearrangements, genetic inactivation of all Kdm4 family members blunted leukemia development while inactivation of Kdm4c alone showed minor effects regarding proliferation of leukemic cells [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms

et al. 2022

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Mutations of the JAK2 gene are frequent aberrations in the aging hematopoietic system and in myeloid neoplasms. While JAK-inhibitors efficiently reduce hyperinflammation induced by the constitutively active mutated JAK2 kinase, the malignant clone and abundance of mutated cells remains rather unaffected. Here, we sought to assess for genetic vulnerabilities of JAK2-mutated clones. We identified lysine-specific demethylase KDM4C as a selective genetic dependency that persists upon JAK-inhibitor treatment. Genetic inactivation of KDM4C in human and murine JAK2-mutated cells resulted in loss of cell competition and reduced proliferation. These findings led to reduced disease penetrance and improved survival in xenograft models of human JAK2-mutated cells. KDM4C deleted cells showed alterations in target histone residue methylation and target gene expression, resulting in induction of cellular senescence. In summary, these data establish KDM4C as a specific dependency and therapeutic target in JAK2-mutated cells that is essential for oncogenic signaling and prevents induction of senescence.

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GASC1 promotes hepatocellular carcinoma progression by inhibiting the degradation of ROCK2

Cited by 8 publications

References 60 publications

KDM4C silencing inhibits cell migration and enhances radiosensitivity by inducing CXCL2 transcription in hepatocellular carcinoma

KDM4C silencing inhibits cell migration and enhances radiosensitivity by inducing CXCL2 transcription in hepatocellular carcinoma

Genetic heterogeneity of liver cancer stem cells

Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms

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