SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A

Xu, Weihua; Jiang, Kanqiu; Shen, Meifen; Qian, Yongyue; Yong, Peng

doi:10.1515/hsz-2014-0284

Cited by 44 publications

(41 citation statements)

References 34 publications

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“…More importantly, one study also showed that Sirt2 Ϫ/Ϫ mice formed tumors in multiple tissues and that the incidence of the tumors increased slowly with age (21). Previous studies also showed that SIRT2 was significantly downregulated in non-small cell lung cancer (23,25,56). Our study showed that HRD1 2CA mutant C291, 294A was used.…”

Section: Discussionsupporting

confidence: 57%

E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation

Liu

Zeng

et al. 2020

Molecular and Cellular Biology

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The NAD-dependent histone deacetylase sirtuin 2 (SIRT2) plays critical roles in mitosis and cell cycle progression and recently was shown to suppress tumor growth and to be downregulated in several types of cancers. However, the underlying mechanism of SIRT2 downregulation remains unknown. In this study, using bioinformatics, gene expression profiling, protein overexpression approaches, and cell migration assays, we showed that E3 ubiquitin ligase 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase degradation 1 (HRD1) interacts with SIRT2 and promotes its ubiquitination and degradation. Furthermore, we found that HRD1 deficiency induces SIRT2 upregulation and inhibits the growth and tumor formation of lung cancer cells both in vitro and in vivo. Of note, we observed that SIRT2 expression is downregulated in human lung cancer and also negatively correlates with HRD1 expression in these cancers. Additionally, we found that patients with lung adenocarcinoma having lower HRD1 or higher SIRT2 expression levels tend to survive longer. On the basis of these results, we propose a mechanism of lung tumorigenesis that involves HRD1-mediated downregulation of SIRT2 and suggest that interventions targeting HRD1 activity could be a potential therapeutic strategy to treat patients with lung cancer.

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Section: Discussionsupporting

confidence: 57%

E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation

Liu

Zeng

et al. 2020

Molecular and Cellular Biology

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“…However, little is known about how JMJD2A is regulated. One recent report showed that expression of JMJD2A is suppressed by tumor suppressor sirt2 [51]. Moreover, as mentioned above, the stability of JMJD2A is regulated by ubiquitination [11,13,39].…”

Section: Discussionmentioning

confidence: 99%

SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication

Yang¹,

Campbell

Chang

2017

PLoS Pathog

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Small ubiquitin-like modifier (SUMO) modification of chromatin has profound effects on transcription regulation. By using Kaposi’s sarcoma associated herpesvirus (KSHV) as a model, we recently demonstrated that epigenetic modification of viral chromatin by SUMO-2/3 is involved in regulating gene expression and viral reactivation. However, how this modification orchestrates transcription reprogramming through targeting histone modifying enzymes remains largely unknown. Here we show that JMJD2A, the first identified Jumonji C domain-containing histone demethylase, is the histone demethylase responsible for SUMO-2/3 enrichment on the KSHV genome during viral reactivation. Using in vitro and in vivo SUMOylation assays, we found that JMJD2A is SUMOylated on lysine 471 by KSHV K-bZIP, a viral SUMO-2/3-specific E3 ligase, in a SUMO-interacting motif (SIM)-dependent manner. SUMOylation is required for stabilizing chromatin association and gene transactivation by JMJD2A. These finding suggest that SUMO-2/3 modification plays an essential role in the epigenetic regulatory function of JMJD2A. Consistently, hierarchical clustering analysis of RNA-seq data showed that a SUMO-deficient mutant of JMJD2A was more closely related to JMJD2A knockdown than to wild-type. Our previous report demonstrated that JMJD2A coated and maintained the “ready to activate” status of the viral genome. Consistent with our previous report, a SUMO-deficient mutant of JMJD2A reduced viral gene expression and virion production. Importantly, JMJD2A has been implicated as an oncogene in various cancers by regulating proliferation. We therefore further analyzed the role of SUMO modification of JMJD2A in regulating cell proliferation. Interestingly, the SUMO-deficient mutant of JMJD2A failed to rescue the proliferation defect of JMJD2A knockdown cells. Emerging specific inhibitors of JMJD2A have been generated for evaluation in cancer studies. Our results revealed that SUMO conjugation mediates an epigenetic regulatory function of JMJD2A and suggests that inhibiting JMJD2A SUMOylation may be a novel avenue for anti-cancer therapy.

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“…SIRT2 acts as a tumor suppressor gene in human gliomas through the regulation of microtubule network [15]. SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A [16]. SIRT2 inhibits non-small cell lung cancer cell growth through impairing Skp2-mediated p27 [17].…”

Section: Discussionmentioning

confidence: 99%

A variant in SIRT2 gene 3′-UTR is associated with susceptibility to colorectal cancer

et al. 2017

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SIRT2 is a member of sirtuin family and is associated with cell growth in various cancers. In this study, we searched for variants in functional region of SIRT2 gene and identify rs2015 and rs2241703 in the 3′UTR with minor allele frequency >0.05 in Chinese Han Beijing population from 1000 Genomes Project. We then genotyped these two variants in 842 colorectal cancer (CRC) patients and 1,718 healthy controls using Taqman genotyping assay. Association between variants and risk of CRC is calculated using logistic regression adjusted for sex and age. We found that rs2015C was significantly associated with increased risk of CRC. Compared with CC genotype carriers, CA genotype and AA genotype carriers were associated with CRC susceptibility with OR being 0.79 (95% CI: 0.65–0.96, P = 0.019) and 0.73 (95% CI: 0.58–0.92, P = 0.009), respectively. When stratified by sex and age, significant associations were observed only in males (OR = 0.82, 95% CI: 0.71–0.96, P = 0.010) for rs2015, but not females (OR = 0.90, 95% CI: 0.73–1.10, P = 0.287). It is suggested that the sequence including rs2015C allele lies within a binding site for the full seed region of hsa-miR-376a-5p. Through a systematic interrogate of variants in the functional region of SIRT2 gene, we identified rs2015 was significantly associated with CRC susceptibility, providing new insights into the carcinogenesis of CRC.

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SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A

Cited by 44 publications

References 34 publications

E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation

E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation

SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication

A variant in SIRT2 gene 3′-UTR is associated with susceptibility to colorectal cancer

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