TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

Groner, Anna C.; Cato, Laura; Tribolet-Hardy, Jonas de; Bernasocchi, Tiziano; Janoušková, Hana; Melchers, Diana; Houtman, René; Cato, Andrew C. B.; Tschopp, Patrick; Gu, Lei; Corsinotti, Andrea; Zhong, Qing; Fankhauser, Christian Daniel; Fritz, Christine; Poyet, Cédric; Wagner, Ulrich; Guo, Tiannan; Aebersold, Ruedi; Garraway, Levi A.; Wild, Peter J.; Theurillat, Jean-Philippe; Brown, Myles

doi:10.1016/j.ccell.2016.04.012

Cited by 225 publications

(228 citation statements)

References 57 publications

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“…TRIM proteins have been shown to have important roles in various cellular processes, including cell development, proliferation and differentiation. Several TRIM members, such as TRIM24 and TRIM29, participate in the progression of solid tumors by inducing ubiquitylation of their downstream targets (Dükel et al, 2016;Groner et al, 2016). For example, TRIM65 is upregulated in lung cancer and promotes tumor growth via ubiquitylation of p53 (also known as TP53) to inhibit its antitumor activity Wang et al, 2016).…”

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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“…FKBP51, another coactivator, stabilizes the HSP90-AR complex, enhancing the ability of AR molecules to bind to androgen [46]. Finally, TRIM24 is a transcriptional activator that has been shown to contribute to AR signaling under castrate androgen levels in SPOP mutants and in CRPC [47] (Fig. 1(D)).…”

Section: Resistance To Androgen Ablation In Hormone-sensitive Diseasementioning

confidence: 99%

Mechanisms of Therapeutic Resistance in Prostate Cancer

2017

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Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing and combinations. This review outlines our current understanding of mechanisms of therapeutic resistance in progression to and after the development of castration resistance, highlighting targetable and reversible mechanisms of resistance.

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“…Several AR-associated coregulators are overexpressed in CR-CaP, i.e. in presence of AR that has been “re-activated” under ADT, compared to localized CaP (Table 1) (Agoulnik, et al 2006; Balasubramaniam, et al 2013; Comuzzi, et al 2004; Goodwin, et al 2013; Gregory, et al 2001; Groner, et al 2016; Halkidou, et al 2003; Karpf, et al 2009; Logan, et al 2006; Malik, et al 2015; Peng, et al 2008; Puhr, et al 2014; Schrecengost, et al 2014; Varambally, et al 2002). While AR-associated coregulators do regulate AR’s transcriptional output, and some have been claimed to be specific for AR at the time of isolation (Yeh and Chang 1996), it is now clear that their actions are generally not restricted to AR but regulate also other transcription factors.…”

Section: Heterogeneity In the Interaction Between Ar And Its Associatmentioning

confidence: 99%

Rationale for the development of alternative forms of androgen deprivation therapy

Kumari¹,

Senapati²,

Heemers³

2017

Endocrine-Related Cancer

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With few exceptions, the almost 30,000 prostate cancer deaths annually in the United States are due to failure of androgen deprivation therapy. Androgen deprivation therapy prevents ligand-activation of the androgen receptor. Despite initial remission after androgen deprivation therapy, prostate cancer almost invariably progresses while continuing to rely on androgen receptor action. Androgen receptor's transcriptional output, which ultimately controls prostate cancer behavior, is an alternative therapeutic target, but its molecular regulation is poorly understood. Recent insights in the molecular mechanisms by which the androgen receptor controls transcription of its target genes are uncovering gene specificity as well as context-dependency. Heterogeneity in the androgen receptor's transcriptional output is reflected both in its recruitment to diverse cognate DNA binding motifs and in its preferential interaction with associated pioneering factors, other secondary transcription factors and coregulators at those sites. This variability suggests that multiple, distinct modes of androgen receptor action that regulate diverse aspects of prostate cancer biology and contribute differentially to prostate cancer's clinical progression are active simultaneously in prostate cancer cells. Recent progress in the development of peptidomimetics and small molecules, and application of Chem-Seq approaches indicate the feasibility for selective disruption of critical protein-protein and protein-DNA interactions in transcriptional complexes. Here, we review the recent literature on the different molecular mechanisms by which the androgen receptor transcriptionally controls prostate cancer progression, and we explore the potential to translate these insights into novel, more selective forms of therapies that may bypass prostate cancer's resistance to conventional androgen deprivation therapy.

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TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

Cited by 225 publications

References 57 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

Mechanisms of Therapeutic Resistance in Prostate Cancer

Rationale for the development of alternative forms of androgen deprivation therapy

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