Overexpression of HMGA1 deregulates tumor growth via cdc25A and alters migration/invasion through a cdc25A-independent pathway in medulloblastoma

Lau, Kin Mang; Chan, Queeny K.Y.; Pang, Jesse Chung Sean; Ting, Fanny Man; Li, Kay K. W.; Yeung, William S.B.; Cheng, Alfred S.L.; Feng, Hai; Chung, Nellie Yuk Fei; Li, Hiu Ming; Zhou, Lei; Wang, Yin; Mao, Ying; Ng, Ho Keung

doi:10.1007/s00401-011-0934-8

Cited by 21 publications

(24 citation statements)

References 42 publications

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“…HMGA1 is a nonhistone nuclear protein involved in genetic recombination, chromosomal modulation, DNA repair and cell apoptosis (Sumter et al, 2016). Overexpression of HMGA1 in human cancers, such as medulloblastoma, colorectal cancer and HCC, promotes malignant progression via transcriptional regulation of several oncogenes or tumor suppressor genes (Andreozzi et al, 2016;Lau et al, 2012;Liang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

Yang

Zhang

Qing

et al. 2017

Journal of Cell Science

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Deregulation of ubiquitin ligases contributes to the malignant progression of human cancers. Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and has been implicated in human diseases, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unknown. Here, we showed that TRIM65 expression was increased in HCC tissues and associated with poor outcome in two independent cohorts containing 888 patients. In vitro and in vivo data demonstrated that overexpression of TRIM65 promoted cell growth and tumor metastasis, whereas knockdown of TRIM65 resulted in opposite phenotypes. Further studies revealed that TRIM65 exerted oncogenic activities via ubiquitylation of Axin1 to activate the β-catenin signaling pathway. TRIM65 directly bound to Axin1 and accelerated its degradation through ubiquitylation. Furthermore, HMGA1 was identified as an upstream regulator of TRIM65 in HCC cells. In clinical samples, TRIM65 expression was positively correlated with the expression of HMGA1 and nuclear β-catenin. Collectively, our data indicate that TRIM65 functions as an oncogene in HCC. The newly identified HMGA1/TRIM65/β-catenin axis serves as a promising prognostic factor and therapeutic target.

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Section: Introductionmentioning

confidence: 99%

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

Yang

Zhang

Qing

et al. 2017

Journal of Cell Science

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“…Ribosomal protein 3 (RPS3, Table S2) was used as the housekeeping control. Relative gene expression was determined by the ΔΔC T method [32].…”

Section: Methodsmentioning

confidence: 99%

Hsa-miRNA-765 as a Key Mediator for Inhibiting Growth, Migration and Invasion in Fulvestrant-Treated Prostate Cancer

Leung

Chan

et al. 2014

PLoS ONE

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Fulvestrant (ICI-182,780) has recently been shown to effectively suppress prostate cancer cell growth in vitro and in vivo. But it is unclear whether microRNAs play a role in regulating oncogene expression in fulvestrant-treated prostate cancer. Here, this study reports hsa-miR-765 as the first fulvestrant-driven, ERβ-regulated miRNA exhibiting significant tumor suppressor activities like fulvestrant, against prostate cancer cell growth via blockage of cell-cycle progression at the G2/M transition, and cell migration and invasion possibly via reduction of filopodia/intense stress-fiber formation. Fulvestrant was shown to upregulate hsa-miR-765 expression through recruitment of ERβ to the 5′-regulatory-region of hsa-miR-765. HMGA1, an oncogenic protein in prostate cancer, was identified as a downstream target of hsa-miR-765 and fulvestrant in cell-based experiments and a clinical study. Both the antiestrogen and the hsa-miR-765 mimic suppressed HMGA1 protein expression. In a neo-adjuvant study, levels of hsa-miR-765 were increased and HMGA1 expression was almost completely lost in prostate cancer specimens from patients treated with a single dose (250 mg) of fulvestrant 28 days before prostatectomy. These findings reveal a novel fulvestrant signaling cascade involving ERβ-mediated transcriptional upregulation of hsa-miR-765 that suppresses HMGA1 protein expression as part of the mechanism underlying the tumor suppressor action of fulvestrant in prostate cancer.

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“…Netropsin can suppress the growth of HMGA1 expressing medulloblastoma cells (56). The data presented here show that targeting HMGA2 may be therapeutically beneficial in AT/RT.…”

Section: Discussionmentioning

confidence: 99%

The Chromatin-Modifying Protein HMGA2 Promotes Atypical Teratoid/Rhabdoid Cell Tumorigenicity

Kaur

Hütt-Cabezas

Weingart

et al. 2015

J Neuropathol Exp Neurol

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Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive pediatric central nervous system tumor. The poor prognosis of AT/RT warrants identification of novel therapeutic targets and strategies. High mobility group A2 (HMGA2) is a developmentally important chromatin modifying protein that positively regulates tumor growth, self-renewal and invasion in other cancer types. HMGA2 was recently identified as being upregulated in AT/RT tissue, but the role of HMGA2 in brain tumors remains unknown. We used lentiviral short hairpin RNA to suppress HMGA2 in AT/RT cell lines and found that loss of HMGA2 led to decreased cell growth, proliferation, colony formation and increased apoptosis. We also found that suppression of HMGA2 negatively affected in vivo orthotopic xenograft tumor growth, more than doubling median survival of the mice from 58 days to 153 days. Our results indicate a role for HMGA2 in AT/RT in vitro and in vivo and demonstrate that HMGA2 is a potential therapeutic target in these lethal pediatric tumors.

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Overexpression of HMGA1 deregulates tumor growth via cdc25A and alters migration/invasion through a cdc25A-independent pathway in medulloblastoma

Cited by 21 publications

References 42 publications

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

Hsa-miRNA-765 as a Key Mediator for Inhibiting Growth, Migration and Invasion in Fulvestrant-Treated Prostate Cancer

The Chromatin-Modifying Protein HMGA2 Promotes Atypical Teratoid/Rhabdoid Cell Tumorigenicity

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