ARID1A prevents squamous cell carcinoma initiation and chemoresistance by antagonizing pRb/E2F1/c-Myc-mediated cancer stemness

Luo, Qingyu; Wu, Xiaowei; Chang, Wan; Zhao, Pengfei; Nan, Yabing; Zhu, Xiaolin; Katz, Jonathan P.; Su, Dan; Liu, Zhihua

doi:10.1038/s41418-019-0475-6

Cited by 35 publications

(14 citation statements)

References 54 publications

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“…Thus, inhibition of GLS1 with the novel inhibitor CB839 (Telaglenastat) has been proposed as a novel strategy for the treatment of ARID1Amutated OCCC 19 . This is conceptually supported by findings from our team 16 and others [20][21][22][23][24] showing that in OCCC, ARID1A loss is followed by increased expression levels of c-Myc, which is known to be an important regulator of GLS1 expression. .…”

Section: Introductionsupporting

confidence: 68%

GLS1 is a protective factor rather than a molecular target in ARID1A-mutated ovarian clear cell carcinoma

Clemente

Nelson

Erickson

et al. 2021

Preprint

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Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is kidney isoform of glutaminase (Glutaminase 1, GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and also chemoresistant ovarian cancer histotype. In OCCC derived cells in vitro as well in mouse models, loss of ARID1A leads to upregulation of GLS1. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. If validated, testing of ARID1A would provide a new time and cost-effective predictive biomarker for stratification of OCCC patients based on the likelihood to respond to CB839 treatment. We found that in clinical specimens of OCCC GLS1 overexpression is not correlated to ARID1A loss; on the contrary, this overexpression is actually associated with better outcome. Our findings suggest that in OCCC, GLS1 may be a protective factor and that caution should be taken when considering the use of CB839 to treat OCCC patients.

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Section: Introductionsupporting

confidence: 68%

GLS1 is a protective factor rather than a molecular target in ARID1A-mutated ovarian clear cell carcinoma

Clemente

Nelson

Erickson

et al. 2021

Preprint

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“…Squamous differentiation is observed in 25% of human endometrial cancer and was recently associated with disease recurrence, and it has been observed in mouse models [99][100][101]. ARID1A and SWI/SNF mutations have been shown to promote carcinogenesis of various squamous tumor types [102,103]. We observed that ARID1A mutant UCEC tumors have higher TP63 expression than TP53 mutant tumors.…”

Section: Plos Geneticsmentioning

confidence: 54%

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

et al. 2021

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TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.

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“…The turnover of β-catenin is the critical event in Wnt/β-catenin signaling pathway [ 8 ]. Accumulated β-catenin enters the nucleus and binds to TCF transcription factors to activate the transcription of downstream genes including CD44, MYC and LGR5, which potentiate the stemness of CRC and promotes CRC progression [ 9 – 11 ]. Degradation of β-catenin is mediated by the β-catenin destruction complex, in which APC plays critical roles as it binds to AXIN1 and β-catenin [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway

Liu

Sun

et al. 2021

J Exp Clin Cancer Res

111

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Background Cancer stem cell (CSC)-related chemoresistance leads to poor outcome of the patients with colorectal cancer (CRC). In this study, we identified the chemoresistance-relevant molecules and decipher the involved mechanisms to provide potential therapeutic target for CRC. We focused on Sec62, a novel target with significantly increased expression in chemoresistant CRC tissues, and further investigated its role in the progression of CRC. Methods Through analyzing the differentially-expressed genes between chemoresistant and chemosensitive CRCs, we selected Sec62 as a novel chemoresistance-related target in CRC. The expression and clinical significance of Sec62 were determined by immunoblotting and immunohistochemistry in tissues and cell lines of CRC. The roles of Sec62 in drug resistance, stemness and tumorigenesis were evaluated in vitro and in vivo using functional experiments. GST pull-down, western blot, coimmunoprecipitation and Me-RIP assays were performed to further explore the downstream molecular mechanisms. Results Sec62 upregulation was associated with the chemoresistance of CRC and poor outcome of CRC patients. Depletion of Sec62 sensitized CRC cells to chemotherapeutic drugs. Sec62 promoted the stemness of CRC cells through activating Wnt/β-catenin signaling. Mechanistically, Sec62 bound to β-catenin and inhibited the degradation of β-catenin. Sec62 competitively disrupted the interaction between β-catenin and APC to inhibit the β-catenin destruction complex assembly. Moreover, Sec62 expression was upregulated by the m6A-mediated stabilization of Sec62 mRNA. Conclusions Sec62 upregulated by the METTL3-mediated m6A modification promotes the stemness and chemoresistance of CRC by binding to β-catenin and enhancing Wnt signalling. Thus, m6A modification-Sec62-β-catenin molecular axis might act as therapeutic targets in improving treatment of CRC.

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ARID1A prevents squamous cell carcinoma initiation and chemoresistance by antagonizing pRb/E2F1/c-Myc-mediated cancer stemness

Cited by 35 publications

References 54 publications

GLS1 is a protective factor rather than a molecular target in ARID1A-mutated ovarian clear cell carcinoma

GLS1 is a protective factor rather than a molecular target in ARID1A-mutated ovarian clear cell carcinoma

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway

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