Epigenetic inactivation of the candidate tumor suppressor gene ASC/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target

Liu, Qianling; Jin, Jie; Ying, Jianming; Cui, Yun; Sun, Mengkui; Fan, Yu; Xu, Ben; Zhang, Qian

doi:10.18632/oncotarget.4256

Cited by 29 publications

(32 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ASC-expressing cells exhibited increased apoptosis at a high cell density. ASC has been reported to play an essential role in the intrinsic mitochondrial pathway of apoptosis through a p53-Bax network [27], with the anti-tumorigenic function of ASC being partially regulated by the activation of p53 and p21 signaling [17]. However, experiments with shRNA revealed that the ASC-dependent apoptosis induced at a high cell density in this study was independent of p53 and p21.…”

Section: Discussionmentioning

confidence: 53%

“…Colorectal cancer was enhanced upon genetic deletion of caspase-1 or ASC [14], while ASC-overexpressing lymphoma cells showed reduced metastasis [15]. The understanding of the mechanisms of ASC has progressed as well, with reports of tumorigenesis inhibition in primary melanoma via ASC expression by restricting NF-κB activity [16] and decreased P53- and p21-related cell apoptosis by knockdown of ASC [17]. …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication

Kitazawa¹,

Hida²,

Fujii³

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

ASC (apoptosis-associated speck-like protein containing a CARD) is a key adaptor molecule of inflammasomes that mediates inflammatory and apoptotic signals. Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, although this role remains incompletely defined especially in the context of closely neighboring cell proliferation. As ASC has been confirmed to be silenced by abnormal methylation in HT1080 fibrosarcoma cells as well, this cell line was investigated to characterize the precise role and mechanism of ASC in tumor progression. The effects of ASC were examined using in vitro cell cultures based on comparisons between low and high cell density conditions as well as in a xenograft murine model. ASC overexpression was established by insertion of the ASC gene into pcDNA3 and pMX-IRES-GFP vectors, the latter being packed into a retrovirus and subjected to reproducible competitive assays using parental cells as an internal control, for evaluation of cell viability. p21 and p53 were silenced using shRNA. Cell viability was suppressed in ASC-expressing transfectants as compared with control cells at high cell density conditions in in vitro culture and colony formation assays and in in vivo ectopic tumor formation trials. This suppression was not detected in low cell density conditions. Furthermore, remarkable progression of apoptosis was observed in ASC-introduced cells at a high cell density, but not at a low one. ASC-dependent apoptosis was mediated not by p21, p53, or caspase-1, but rather by cleavage of caspase-9 as well as by suppression of the NF-κB-related X-linked inhibitor-of-apoptosis protein. Caspase-9 cleavage was observed to be dependent on gap junction formation. The remarkable effect of ASC on the induction of apoptosis through caspase-9 and gap junctions revealed in this study may lead to promising new approaches in anticancer therapy.

show abstract

Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication

Kitazawa¹,

Hida²,

Fujii³

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Incidentally, the ectopic expression of ASC in human fibrosarcoma HT-1080 cells in which ASC expression is silenced by epigenetic regulation also resulted in the attenuation of cellular motility in scratch assays (our unpublished data). Liu et al [16] reported that ectopically expressed ASC suppressed RCC cell migration and invasion in 786-0 and A498 cells. Moreover, we demonstrated a higher experimental metastatic ability of ASC-knockdown B16BL6 cells to the lung.…”

Section: Discussionmentioning

confidence: 99%

“…Since Liu et al [16] reported that ASC overexpression suppressed cell migration and invasion in RCC cell lines, we next examined the effects of ASC-knockdown on the cellular motility of B16BL6 cells in scratch assays. Interestingly, cellular motility, or wound healing, was significantly enhanced in ASC-knockdown cells within 14 h of scratching ( Fig.…”

Section: Asc Silencing Significantly Enhanced the Motility Of B16bl6 mentioning

confidence: 99%

“…Other groups have also identified relationships between silencing of the ASC gene by methylation and prognosis in prostate cancer [11,12], glioblastoma [13], hepatocellular carcinoma [14], cervical cancer [15], and others. Recently, Liu et al [16] demonstrated that ASC was epigenetically inactivated in 41.1% of renal cell carcinoma (RCC) and suggested a role of tumor suppressor. Wu et al [17] reported that hypermethylation of the ASC/TMS1 promoter was significantly associated with greater lymph node metastasis, associated with a poor prognosis in patients with gastric cancer, and should be considered as a key prognostic indicator.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Novel role of ASC as a regulator of metastatic phenotype

Okada

Fujii

Matsumura

et al. 2017

Journal of Dermatological Science

View full text Add to dashboard Cite

Novel role of ASC as a regulator of metastatic phenotype

et al. 2016

View full text Add to dashboard Cite

Disorders of cytoskeletal remodeling and signal transduction are frequently involved in cancer progression. In particular, apoptosis‐associated speck‐like protein containing a caspase‐recruitment domain (ASC) has been reported a proapoptotic molecule that is epigenetically silenced in several human cancers. ASC is a well‐characterized adaptor protein involved in the formation of multiprotein oligomers, called inflammasomes, and plays a crucial role in the activation and secretion of interleukin‐1β and interleukin‐18 in innate immune cells. However, the function of ASC in the regulation of tumor progression remains elusive. The present investigation examined the involvement of ASC in cancer progression and the acquisition of metastatic ability. To determine the effect of ASC depletion in in vitro and in vivo model systems, ASC was stably knocked down in B16 murine melanoma cell lines using retroviral transduction of shRNA. ASC suppression increased the motility of B16BL6 cells in scratch assays and augmented invasiveness as assessed by a Matrigel‐coated transwell system. Invadopodia formation and Src phosphorylation level were markedly enhanced in ASC‐knockdown cells as well. Since caspase‐8 has been reported to enhance cellular migration by Tyr380 phosphorylation via Src, we examined Tyr380 phosphorylation of caspase‐8 in ASC‐knockdown cells and found it to be elevated in ASC‐knockdown cells but attenuated by z‐VAD‐fmk or z‐IETD‐fmk. Moreover, ASC ablation increased pulmonary metastasis in mice after intravenous injection of B16BL6 cells. Our cumulative findings indicate that ASC suppresses cancer metastasis and progression via the modulation of cytoskeletal remodeling and the Src‐caspase‐8 signaling pathway.

show abstract

Epigenetic inactivation of the candidate tumor suppressor gene ASC/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target

Cited by 29 publications

References 42 publications

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication

Novel role of ASC as a regulator of metastatic phenotype

Novel role of ASC as a regulator of metastatic phenotype

Contact Info

Product

Resources

About