Distinct HIC1-SIRT1-p53 Loop Deregulation in Lung Squamous Carcinoma and Adenocarcinoma Patients

Tseng, Ruo Chia; Lee, Chin Chu; Hsu, Han Shui; Tzao, Ching; Wang, Yi‐Ching

doi:10.1593/neo.09470

Cited by 89 publications

(78 citation statements)

References 28 publications

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“…A previous study reported that patients with SCC had significantly higher low-acetylated p53 status compared with patients with AD (P=0.012), and that low-acetylated p53 was associated with poorer survival relative to that of patients with acetylated p53 (13). These findings indicate that p53 deacetylation may play a role in lung tumorigenesis, particularly for SCC patients.…”

Section: A B C Dmentioning

confidence: 71%

“…To the best of our knowledge, the current study is the first to report on the association between SIRT1 and HMGA1 expression in lung cancer, although their respective roles in tumorigenesis have been widely studied previously (12)(13)(14)(15)26). HMGA1 proteins are reported to be important in the process of carcinogenesis, based on the HMGA1-p53 interaction.…”

Section: A B C Dmentioning

confidence: 85%

“…The region of the SIRT1 promoter containing the p53-binding sequence also contains a binding site for the transcriptional repressor HIC1 (12). In addition, dysregulation of the HIC1-SIRT1-p53 loop may be involved in lung tumorigenesis and disease outcome (13). Taken together, these results indicate there is a mechanism connecting the expression of SIRT1 and HMGA1.…”

Section: A B C Dmentioning

confidence: 86%

“…These findings indicate that p53 deacetylation may play a role in lung tumorigenesis, particularly for SCC patients. The different status of p53 acetylation/deacetylation in patients with lung AD and SCC may be caused by the distinct deregulation of SIRT1 epigenetic control (13). In addition, AD is now classified according to its predominant pattern following comprehensive histological subtyping into lepidic, acinar, papillary, solid, mucinous, mixed muciniusand nonmucinous adenocarcinoma, and other subtype AD, based on the WHO classification criteria (33).…”

Section: A B C Dmentioning

confidence: 99%

“…Numerous studies have demonstrated that SIRT1 is overexpressed in various types of cancer, including breast (4), liver (5), prostate (6) and lung cancers (7,8), and that SIRT1 inhibitors are able to suppress tumor growth. SIRT1 is responsible for the deacetylation of various transcription factors that are involved in stress responses and apoptosis, including p53 (9), Ku70 (10), Nuclear factor kB (8), Forkhead box protein O (11) and Hypermethylated in cancer 1 (HIC1) (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

Lin¹,

Peng²

2015

Oncology Letters

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Abstract. The roles of Silent mating type information regulation 2 homolog 1 (SIRT1) and High mobility group A1 (HMGA1) in human diseases have been extensively studied separately; however, to the best of our knowledge, the current study is the first to report on their interrelationship in lung cancer. The association of SIRT1 and HMGA1 in non-small cell lung cancer (NSCLC) was investigated by evaluating their expression and prognostic significance in 260 patients with NSCLC using immunohistochemistry. SIRT1 and HMGA1 expression were found to be significantly correlated with each other (P<0.001), and both were significantly associated with clinicopathological parameters, including histological type and degree of differentiation. In squamous cell carcinoma (SCC), SIRT1 + specimens were significantly associated with shorter overall survival (OS) time (P=0.019). However, in patients with adenocarcinoma (AD), no association was identified between SIRT1 and OS. In addition, HMGA1 + specimens were significantly associated with poor differentiation (P=0.028), and were more frequent in SCC than AD (P=0.015). However, HMGA1 was not associated with OS on univariate Cox regression analysis or Kaplan-Meier analysis (both P>0.05). SIRT1/HMGA1 coexpression was significantly associated with male gender (P=0.016), and moderately and poorly differentiated histological grade (P=0.025). The findings indicate that SIRT1 and HMGA1 may have significant effects during tumor progression in NSCLC, particularly in patients with SCC, and are potentially useful as prognostic indicators for patients with NSCLC.

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Section: A B C Dmentioning

confidence: 71%

Section: A B C Dmentioning

confidence: 85%

Section: A B C Dmentioning

confidence: 86%

Section: A B C Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

Lin¹,

Peng²

2015

Oncology Letters

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HIC2, a new transcription activator of SIRT1

et al. 2019

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The protein deacetylase SIRT1 is crucial to numerous physiological processes, such as aging, metabolism, and autoimmunity, and is repressed by various transcription factors, including HIC1. Conversely, we found that HIC2, which is highly homologous to HIC1, is a transcriptional activator of SIRT1 due to opposite activity of the intermediate domains of the two homologs. Importantly, this relationship between HIC2 and SIRT1 could be important for cardiac development, where both proteins are implicated. Here, we assessed whether ectopic expression of HIC2, and subsequent upregulation of SIRT1, might decrease apoptosis in H9c2 cardiomyocytes under simulated ischemia/reperfusion (I/R) injury conditions. Our results demonstrate that unlike its structural homolog HIC1, HIC2 is a pivotal transcriptional activator of SIRT1 and, consequently, may protect the heart from I/R injury.

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A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53

et al. 2012

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Although ∼50% of all types of human cancers harbour wild-type TP53, this p53 tumour suppressor is often deactivated through a concerted action by its abnormally elevated suppressors, MDM2, MDMX or SIRT1. Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro. Remarkably, INZ inhibits cell proliferation, induces senescence and tumour-specific apoptosis, and represses the growth of xenograft tumours derived from p53-harbouring H460 and HCT116 cells without causing apparent toxicity to normal tissues and the tumour-bearing SCID mice. Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.

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Distinct HIC1-SIRT1-p53 Loop Deregulation in Lung Squamous Carcinoma and Adenocarcinoma Patients

Cited by 89 publications

References 28 publications

Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

HIC2, a new transcription activator of SIRT1

A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53

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