Browsing by Author "Ho, Chun-Ming"

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HDAC Inhibitors Augmented Cell Migration and Metastasis through Induction of PKCs Leading to Identification of Low Toxicity Modalities for Combination Cancer Therapy
(2012-09-01)
Lin, Kuen-Tyng
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Wang, Yi-Wei
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Chen, Chiung-Tong
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Ho, Chun-Ming
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Su, Wen-Hui
Purpose: Histone deacetylase inhibitors (HDACi) are actively explored as new-generation epigenetic drugs but have low efficacy in cancer monotherapy. To reveal new mechanism for combination therapy, we show that HDACi induce cell death but simultaneously activate tumor-progressive genes to ruin therapeutic efficacy. Combined treatments to target tumorigenesis and HDACi-activated metastasis with low toxic modalities could develop new strategies for long-term cancer therapy. Experimental Design: Because metastasis is the major cause of cancer mortality, we measured cell migration activity and profiled metastasis-related gene expressions in HDACi-treated cancer cells. We developed low toxic combination modalities targeting tumorigenesis and HDACi-activated metastasis for preclinical therapies in mice. Results: We showed that cell migration activity was dramatically and dose dependently enhanced by various classes of HDACi treatments in 13 of 30 examined human breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was also enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs and downstream substrates along with upregulated proapoptotic p21. For targeting tumorigenesis and metastasis with immediate clinical impact, we showed that new modalities of HDACi combined drugs with PKC inhibitory agent, curcumin or tamoxifen, not only suppressed HDACi-activated tumor progressive proteins and cell migration in vitro but also inhibited tumor growth and metastasis in vivo. Conclusion: Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease. Clin Cancer Res; 18(17); 4691-701. (C)2012 AACR.
IGDB.NSCLC: integrated genomic database of non-small cell lung cancer
(2012-01-01)
Kao, Sen
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Shiau, Cheng-Kai
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Gu, De-Leung
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Ho, Chun-Ming
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Su, Wen-Hui
Lung cancer is the most common cause of cancer-related mortality with more than 1.4 million deaths per year worldwide. To search for significant somatic alterations in lung cancer, we analyzed, integrated and manually curated various data sets and literatures to present an integrated genomic database of non-small cell lung cancer (IGDB. NSCLC, http://igdb.nsclc.ibms.sinica.edu.tw). We collected data sets derived from hundreds of human NSCLC (lung adenocarcinomas and/or squamous cell carcinomas) to illustrate genomic alterations [chromosomal regions with copy number alterations (CNAs), gain/loss and loss of heterozygosity], aberrant expressed genes and microRNAs, somatic mutations and experimental evidence and clinical information of alterations retrieved from literatures. IGDB. NSCLC provides user friendly interfaces and searching functions to display multiple layers of evidence especially emphasizing on concordant alterations of CNAs with co-localized altered gene expression, aberrant microRNAs expression, somatic mutations or genes with associated clinicopathological features. These significant concordant alterations in NSCLC are graphically or tabularly presented to facilitate and prioritize as the putative cancer targets for pathological and mechanistic studies of lung tumorigenesis and for developing new strategies in clinical interventions.
Mutations in NOTCH1 and nucleotide excision repair genes are correlated with prognosis of hepatitis B virus-associated hepatocellular carcinoma
(2018-01-01)
Su, Wen-Hui
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Jou, Yuh-Shan
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Zhang, Jia-Hao
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Ho, Chun-Ming
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Tai, Dar-In
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related mortality because of its poor prognosis. Therefore, identifying targetable genetic mutations and mutational signatures associated with prognosis and treatment strategies are needed. Ultra-deep sequencing of 409 cancer genes using formalin-fixed paraffin-embedded tissue from 33 male patients with hepatitis B virus-associated HCC was performed to identify mutational signatures associated with the prognosis of HCC. A total of 47 genes were found to be mutated in more than 10% of patients. Chromatin remodeling genes were overrepresented in the mutation profile. We found patient survival was associated with mutations in NOTCH1 and the nucleotide excision repair genes which have not been described previously in HCC. From the mutation profile, six patients were eligible for Sorafenib treatment. Among the remaining patients, 7 patients had mutations in genes that are targets for other cancer drugs and 16 patients had mutations in potentially targetable genes. Only one patient carried no potential drug target. We identified mutational signatures associated with the patient survival of HCC. The findings may facilitate identifying subgroups of patients with a poor prognosis as well as potential drug targets for use in personalized strategies for HCC treatment.
PSPC1 mediates TGF-beta 1 autocrine signalling and Smad2/3 target switching to promote EMT, stemness and metastasis
(2018-04-01)
Yeh, Hsi-Wen
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Hsu, En-Chi
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Lee, Szu-Shuo
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Lang, Yaw-Dong
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Lin, Yuh-Charn
Activation of metastatic reprogramming is critical for tumour metastasis. However, more detailed knowledge of the underlying mechanism is needed to enable targeted intervention. Here, we show that paraspeckle component 1 (PSPC1), identified in an aberrant 13q12.11 locus, is upregulated and associated with poor survival in patients with cancer. PSPC1 promotes tumorigenesis, epithelial-to-mesenchymal transition (EMT), stemness and metastasis in multiple cell types and in spontaneous mouse cancer models. PSPC1 is the master activator for transcription factors of EMT and stemness and accompanies c-Myc activation to facilitate tumour growth. PSPC1 increases transforming growth factor-ss 1 (TGF-ss 1) secretion through an interaction with phosphorylated and nuclear Smad2/3 to potentiate TGF-ss 1 autocrine signalling. Moreover, PSPC1 acts as a contextual determinant of the TGF-ss 1 pro-metastatic switch to alter Smad2/3 binding preference from tumour-suppressor to pro-metastatic genes. Having validated the PSPC1-Smads-TGF-ss 1 axis in various cancers, we conclude that PSPC1 is a master activator of prometastatic switches and a potential target for anti-metastasis drugs.
PSPC1-interchanged interactions with PTK6 and beta-catenin synergize oncogenic subcellular translocations and tumor progression
(2019-12-16)
Lang, Yaw-Dong
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Chen, Hsin-Yi
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Ho, Chun-Ming
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Shih, Jou-Ho
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Hsu, En-Chi
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of p-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/beta-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/beta-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/beta-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.