VHL-HIF-2α axis-induced SMYD3 upregulation drives renal cell carcinoma progression via direct trans-activation of EGFR

Liu, Cheng; Liu, Li; Wang, Kun; Li, Xiaofeng; Ge, Liyuan; Ma, Runzhuo; Fan, Yi‐Ming; Li, Luchao; Liu, Zhengfang; Qiu, Min; Hao, Yichang; Shi, Zhenfeng; Xia, Chuanyou; Strååt, Klas; Huang, Yi; Ma, Lulin; Xu, Dawei

doi:10.1038/s41388-020-1291-7

Cited by 27 publications

(18 citation statements)

References 44 publications

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“…= 40) was identified as part of the CRSO core RS. SMYD3 is a member of the histone lysine methyltransferases enzyme family, and upregulates transcription of a plethora of oncogenes in multiple cancer types, including CDK2 and MMP2 in hepatocellular carcinomas (Wang et al, 2019), BCLAF1 in bladder cancer (Shen et al, 2016), androgen receptors in prostate cancer (Liu et al, 2013), EGFR in renal cell carcinoma (Liu et al, 2020a), and MYC and CTNNB1 in colon and liver cancers (Sarris et al, 2016). Mazur et al (2014) showed that SMYD3 methylation of MAP3K2 leads to upregulation of MAP kinase signaling and promotes carcinogenesis in RAS mutated lung and pancreatic cancers.…”

Section: Resultsmentioning

confidence: 99%

Identifying modules of cooperating cancer drivers

Klein

Cannataro

Townsend

et al. 2021

Molecular Systems Biology

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Identifying cooperating modules of driver alterations can provide insights into cancer etiology and advance the development of effective personalized treatments. We present Cancer Rule Set Optimization (CRSO) for inferring the combinations of alterations that cooperate to drive tumor formation in individual patients. Application to 19 TCGA cancer types revealed a mean of 11 core driver combinations per cancer, comprising 2-6 alterations per combination and accounting for a mean of 70% of samples per cancer type. CRSO is distinct from methods based on statistical cooccurrence, which we demonstrate is a suboptimal criterion for investigating driver cooperation. CRSO identified well-studied driver combinations that were not detected by other approaches and nominated novel combinations that correlate with clinical outcomes in multiple cancer types. Novel synergies were identified in NRAS-mutant melanomas that may be therapeutically relevant. Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition. CRSO is available at https://github.com/ mikekleinsgit/CRSO/.

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Section: Resultsmentioning

confidence: 99%

Identifying modules of cooperating cancer drivers

Klein

Cannataro

Townsend

et al. 2021

Molecular Systems Biology

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“…= 40) was identified as part of the CRSO core RS. SMYD3 is a member of the histone lysine methyltransferases enzyme family, and upregulates transcription of a plethora of oncogenes in multiple cancer types, including CDK2 and MMP2 in hepatocellular carcinomas [50], BCLAF1 in bladder cancer [51], androgen receptors in prostate cancer [52], EGFR in renal cell carcinoma [53] and MYC and CTNNB1 in colon and liver cancers [54]. Mazur et al showed that SMYD3 methylation of MAP3K2 leads to upregulation of MAP kinase signaling and promotes carcinogenesis in RAS mutated lung and pancreatic cancers [55].…”

Section: Novel Melanoma Combinations Detected By Crsomentioning

confidence: 99%

Identifying Modules of Cooperating Cancer Drivers

Klein

Cannataro

Townsend

et al. 2020

Preprint

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AbstractIdentifying cooperating modules of driver alterations can provide biological insights to cancer causation and would advance the development of effective personalized treatments. We present Cancer Rule-Set Optimization (CRSO) for inferring the combinations of alterations that cooperate to drive tumor formation in individual patients. Application to 19 TCGA cancer types found a mean of 11 core driver combinations per cancer, comprising 2-6 alterations per combination, and accounting for a mean of 70% of samples per cancer. CRSO departs from methods based on statistical cooccurrence, which we demonstrate is a suboptimal criterion for investigating driver cooperation. CRSO identified well-studied driver combinations that were not detected by other approaches and nominated novel combinations that correlate with clinical outcomes in multiple cancer types. Novel synergies were identified in NRAS-mutant melanomas that may be therapeutically relevant. Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition. CRSO is available at https://github.com/mikekleinsgit/CRSO/.

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“…SMYD3, functioning as methyltransferase, plays a pivotal role in methylation of targeted proteins ( 39 ). Many studies have demonstrated that SMYD3 acts as an oncogene in hepatocellular carcinoma, breast cancer, ovarian cancer, and renal cell carcinoma, in which SMYD3 regulates downstream targets involved in proliferation and metastasis ( 40 – 43 ). Lobo et al.…”

Section: Discussionmentioning

confidence: 99%

Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway

Liu

Kou

et al. 2021

Front. Oncol.

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The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

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VHL-HIF-2α axis-induced SMYD3 upregulation drives renal cell carcinoma progression via direct trans-activation of EGFR

Cited by 27 publications

References 44 publications

Identifying modules of cooperating cancer drivers

Identifying modules of cooperating cancer drivers

Identifying Modules of Cooperating Cancer Drivers

Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway

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