Acquired Resistance with Epigenetic Alterations Under Long-Term Antiangiogenic Therapy for Hepatocellular Carcinoma

Ohata, Yoshiteru; Shimada, Shu; Akiyama, Yoshimitsu; Mogushi, Kaoru; Nakao, Keisuke; Matsumura, Satoshi; Aihara, Arihiro; Mitsunori, Yusuke; Ban, Daisuke; Ochiai, Takanori; Kudo, Akira; Arii, Shigeki; Tanabe, Minoru; Tanaka, Shinji

doi:10.1158/1535-7163.mct-16-0728

Cited by 39 publications

(27 citation statements)

References 27 publications

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“…We showed that metastatic potentials and gene expression profiles of CSC are regulated by histone modifications for open‐bivalent‐closed chromatin statuses . In our recent studies, sorafenib‐resistant HCC was shown to acquire in vivo CSC features with histone modification . We identified that H3K4me3 and H3K27ac levels were globally elevated in HCC cells surviving under the inhibition of angiogenesis, providing the first evidence that dynamic epigenetic states of CSC could be influenced by modulating the tumor microenvironment in vivo.…”

Section: Cancer Stemness Reprogramming As Therapeutic Resistancementioning

confidence: 86%

Precision medicine based on surgical oncology in the era of genome‐scale analysis and genome editing technology

Tanaka

2018

Annals of Gastroent Surgery

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Accumulated evidence suggests that multiple molecular and cellular interactions promote cancer evolution in vivo. Surgical oncology is of growing significance to a comprehensive understanding of the malignant diseases for therapeutic application. We have analyzed more than 1000 clinical samples from surgically resected tissue to identify molecular biomarkers and therapeutic targets for advanced malignancies. Cancer stemness and mitotic instability were then determined as the essential predictors of aggressive phenotype with poor prognosis. Recently, whole genome/exome sequencing showed a mutational landscape underlying phenotype heterogeneity in caners. In addition, integrated genomic, epigenomic, transcriptomic, metabolic, proteomic and phenomic analyses elucidated several molecular subtypes that cluster in liver, pancreatic, biliary, esophageal and gastroenterological cancers. Identification of each molecular subtype is expected to realize the precise medicine targeting subtype‐specific molecules; however, there are obstacle limitations to determine matching druggable targets or synthetic lethal interactions. Current breakthroughs in genome editing technology can provide us with unprecedented opportunity to recapitulate subtype‐specific pathophysiology in vitro and in vivo. Given a great potential, on‐demand editing system can design actionable strategy and revolutionize precision cancer medicine based on surgical oncology.

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Section: Cancer Stemness Reprogramming As Therapeutic Resistancementioning

confidence: 86%

Precision medicine based on surgical oncology in the era of genome‐scale analysis and genome editing technology

Tanaka

2018

Annals of Gastroent Surgery

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“…Epigenetic alterations were employed as pivotal mediators of cancer development and drug resistance [25][26][27][28][29]. Histone lysine methylation, maintains by lysine methyltransferases and lysine demethylase, has been involved in both transcriptional repression (H3K9, H3K27 and H4K20) and activation (H3K4, H3K36 and H3K79) [13,30].…”

Section: Discussionmentioning

confidence: 99%

SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma

Xia

et al. 2020

Preprint

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Background: Sorafenib, the approved first-line chemotherapy drug for HCC, remains the key treatment agent which can effectively improve the survival rate of advanced HCC patients. However, the sorafenib primary resistance limits the application of sorafenib for HCC treatment. The aims of current study are to explore the role and mechanism of SETD1A (Histone Lysine Methyltransferase SET Domain Containing 1A) in sorafenib primary resistance. Methods: The expression of SETD1A in HCC was analyzed by Gene Expression Profiling Interactive Analysis. The survival of HCC patients was analyzed by KM plotter: Kaplan-Meier Plotter. Western Blot and Real-time qPCR were performed to measure the protein and mRNA levels, respectively. Cell counting kit-8 assay and colony formation assay were performed to determine cell viability and proliferation. Propidium Iodide and Trypan Blue staining assays were performed to investigate cell death. Results: Here, we showed that the expression of SETD1A was markedly upregulated in both HCC cell lines and tumor tissues compared to normal hepatocytes and corresponding non-tumor liver tissues, respectively. The patients who had higher level of SETD1A underwent lower survival rate of overall and sorafenib treated HCC patients, respectively. In addition, SETD1A expression was positively correlated with the IC50 of sorafenib treated HCC cell lines. Furthermore, we indicated that knockdown of SETD1 augmented proliferation inhibition and cell death induced by sorafenib. SETD1A deficiency impaired YAP phosphorylation and activation. YAP activation contributed to SETD1A mediated sorafenib primary resistance. Conclusions: Taken together, the current study demonstrated that STED1A enhanced YAP activation to induce sorafenib primary resistance in HCC.

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“…Epigenetic alterations were employed as pivotal mediators of cancer development and drug resistance [25][26][27][28]. Histone lysine methylation, maintains by lysine methyltransferases and lysine demethylase, has been involved in both transcriptional repression (H3K9, H3K27 and H4K20) and activation (H3K4, H3K36 and H3K79) [13,29].…”

Section: Discussionmentioning

confidence: 99%

SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma

Xia

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Sorafenib, the approved first-line chemotherapy drug for HCC, remains the key treatment agent which can effectively improve the survival rate of advanced HCC patients. However, the sorafenib primary resistance limits the application of sorafenib for HCC treatment. The aims of current study are to explore the role and mechanism of SETD1A (Histone Lysine Methyltransferase SET Domain Containing 1A) in sorafenib primary resistance. Methods: The expression of SETD1A in HCC was analyzed by Gene Expression Profiling Interactive Analysis. The survival of HCC patients was analyzed by KM plotter: Kaplan-Meier Plotter. Western Blot and Real-time qPCR were performed to measure the protein and mRNA levels, respectively. Cell counting kit-8 assay and colony formation assay were performed to determine cell viability and proliferation. Propidium Iodide and Trypan Blue staining assays were performed to investigate cell death. Results: Here, we showed that the expression of SETD1A was markedly upregulated in both HCC cell lines and tumor tissues compared to normal hepatocytes and corresponding non-tumor liver tissues, respectively. The patients who had higher level of SETD1A underwent lower survival rate of overall and sorafenib treated HCC patients, respectively. In addition, SETD1A expression was positively correlated with the IC 50 of sorafenib treated HCC cell lines. Furthermore, we indicated that knockdown of SETD1 augmented proliferation inhibition and cell death induced by sorafenib. SETD1A deficiency impaired YAP phosphorylation and activation. Conclusions: Taken together, the current study demonstrated that STED1A enhanced YAP activation to induce sorafenib primary resistance in HCC.

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Acquired Resistance with Epigenetic Alterations Under Long-Term Antiangiogenic Therapy for Hepatocellular Carcinoma

Cited by 39 publications

References 27 publications

Precision medicine based on surgical oncology in the era of genome‐scale analysis and genome editing technology

Precision medicine based on surgical oncology in the era of genome‐scale analysis and genome editing technology

SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma

SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma

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