PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation

Chan, Li-Chong; Zhou, Lei; Ng, Kai Yu; Wong, Tin Lok; Lee, Terence; Sharma, Rakesh; Loong, Jane Ho Chun; Ching, Yick–Pang; Yuan, Yunfei; Xie, Dan; Lo, Chung Mau; Man, Kwan; Artegiani, Benedetta; Clevers, Hans; Yan, Helen H.N.; Leung, Suet Yi; Richard, Stéphane; Guan, Xin Yuan; Huen, Michael S.Y.; Ma, Stephanie

doi:10.1016/j.celrep.2018.09.053

Cited by 81 publications

(63 citation statements)

References 39 publications

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“…Specifically, WT C57BL/6J and PRMT6 knockout (PRMT6 −/− ) mice were subjected to DEN+CCL 4 treatment for induction of a fibrosis/inflammation‐associated HCC model that closely mimics the disease in human. Our earlier work found PRMT6 −/− mice to develop bigger HCC tumors than WT mice, while hematoxylin and eosin (H&E) staining also revealed larger areas of tumors in PRMT6 −/− mice compared with controls . Relevant to this current study, we performed immunohistochemistry staining for PRMT6 and p‐ERK1/2 on these xenografted liver sections and analyzed PKM2 localization of these xenografted livers by western blot in dissociated tissues subfractionated for cytoplasmic and nuclear protein.…”

Section: Resultsmentioning

confidence: 72%

“…Recent work from our group has shown PRMT6 to be frequently down‐regulated in human HCC and that PRMT6 functions to regulate cancer initiating and stemness activities . During generation of HCC cells with PRMT6 stably overexpressed or suppressed for these experiments, we observed marked differences in the color of the culture medium.…”

Section: Resultsmentioning

confidence: 79%

“…Our earlier studies found PRMT6 to interact with CRAF on Arg100, and as a result hinder its RAS binding potential and alter its downstream MEK/ERK signaling . There is now ample evidence to suggest that MEK/ERK signaling does alter both phosphorylation and nuclear translocation of PKM2 .…”

Section: Resultsmentioning

confidence: 98%

“…PRMT6 functions by catalyzing the asymmetric dimethylation of arginine (ADMA) residues on proteins. Our previous work found knockdown and overexpression of PRMT6 to lead to a concomitant respective decrease and increase of ADMA, suggesting that the global arginine methyltransferase activity of these cells to be altered . To examine whether PRMT6 confers altered glycolytic properties in HCC through this enzymatic activity, we performed similar functional studies with WT PRMT6 or catalytic methyltransferase inactive mutant PRMT6 VLD:KLA (Supporting Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous work found PRMT6 to be frequently down‐regulated and negatively correlated with aggressive cancer features in human HCC. We also demonstrated a critical repressive function for PRMT6 in the maintenance of HCC cancer stemness by regulating RAS binding and MEK/extracellular signal–regulated kinase (ERK) signaling via methylation of CRAF on arginine 100 (Arg100) . However, whether PRMT6 regulates energy metabolism in cancer cells remains unknown.…”

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confidence: 99%

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CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis–Driven Hepatocarcinogenesis via ERK‐Dependent PKM2 Nuclear Relocalization and Activation

Wong

Tan

et al. 2020

Hepatology

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Background and Aims Most tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain‐of‐function and loss‐of‐function in vitro studies in patient‐derived organoid and cell cultures as well as in vivo positron emission tomography–magnetic resonance imaging animal models, we showed that protein arginine N‐methyltransferase 6 (PRMT6) regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Approach and Results We found PRMT6 to methylate CRAF at arginine 100, interfering with its RAS/RAF binding potential, and therefore altering extracellular signal–regulated kinase (ERK)‐mediated PKM2 translocation into the nucleus. This altered PRMT6‐ERK‐PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical samples. We also identified PRMT6 as a target of hypoxia through the transcriptional repressor element 1‐silencing transcription factor, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof of concept the therapeutic potential of using 2‐deoxyglucose, a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC. Conclusions Our findings indicate that the PRMT6‐ERK‐PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells, and provide a mechanistic link among tumorigenicity, sorafenib resistance, and glucose metabolism.

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis–Driven Hepatocarcinogenesis via ERK‐Dependent PKM2 Nuclear Relocalization and Activation

Wong

Tan

et al. 2020

Hepatology

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Chemotherapy‐Enriched THBS2‐Deficient Cancer Stem Cells Drive Hepatocarcinogenesis through Matrix Softness Induced Histone H3 Modifications

Shea

Wong

et al. 2021

Advanced Science

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The physical microenvironment is a critical mediator of tumor behavior. However, detailed biological and mechanistic insight is lacking. The present study reveals the role of chemotherapy‐enriched CD133+ liver cancer stem cells (CSCs) with THBS2 deficiency. This subpopulation of cells contributes to a more aggressive cancer and functional stemness phenotype in hepatocellular carcinoma (HCC) by remodeling the extracellular matrix (ECM) through the regulation of matrix metalloproteinase (MMP) activity, collagen degradation, and matrix stiffness. The local soft spots created by these liver CSCs can enhance stemness and drug resistance and provide a route of escape to facilitate HCC metastasis. Interestingly, a positive feed‐forward loop is identified where a local soft spot microenvironment in the HCC tumor is enriched with CD133 expressing cells that secrete markedly less ECM‐modifying THBS2 upon histone H3 modification at its promoter region, allowing the maintenance of a localized soft spot matrix. Clinically, THBS2 deficiency is also correlated with low HCC survival, where high levels of CSCs with low THBS2 expression in HCC are associated with decreased collagen fiber deposits and an invasive tumor front. The findings have implications for the treatment of cancer stemness and for the prevention of tumor outgrowth through disseminated tumor cells.

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The PRMT6/PARP1/CRL4B Complex Regulates the Circadian Clock and Promotes Breast Tumorigenesis

Yang

Huang

et al. 2023

Advanced Science

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Circadian rhythms, as physiological systems with self‐regulatory functions in living organisms, are controlled by core clock genes and are involved in tumor development. The protein arginine methyltransferase 6 (PRMT6) serves as an oncogene in a myriad of solid tumors, including breast cancer. Hence, the primary aim of the current study is to investigate the molecular mechanisms by which the PRMT6 complex promotes breast cancer progression. The results show that PRMT6, poly(ADP‐ribose) polymerase 1 (PARP1), and the cullin 4 B (CUL4B)‐Ring E3 ligase (CRL4B) complex interact to form a transcription‐repressive complex that co‐occupies the core clock gene PER3 promoter. Moreover, genome‐wide analysis of PRMT6/PARP1/CUL4B targets identifies a cohort of genes that is principally involved in circadian rhythms. This transcriptional‐repression complex promotes the proliferation and metastasis of breast cancer by interfering with circadian rhythm oscillation. Meanwhile, the PARP1 inhibitor Olaparib enhances clock gene expression, thus, reducing breast carcinogenesis, indicating that PARP1 inhibitors have potential antitumor effects in high‐PRMT6 expression breast cancer.

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PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation

Cited by 81 publications

References 39 publications

CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis–Driven Hepatocarcinogenesis via ERK‐Dependent PKM2 Nuclear Relocalization and Activation

CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis–Driven Hepatocarcinogenesis via ERK‐Dependent PKM2 Nuclear Relocalization and Activation

Chemotherapy‐Enriched THBS2‐Deficient Cancer Stem Cells Drive Hepatocarcinogenesis through Matrix Softness Induced Histone H3 Modifications

The PRMT6/PARP1/CRL4B Complex Regulates the Circadian Clock and Promotes Breast Tumorigenesis

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