HIC2, a new transcription activator of SIRT1

Abstract

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.

Hypermethylation of HIC2 is a potential prognostic biomarker and tumor suppressor of glioma based on bioinformatics analysis and experiments

“…HIC2 was found to be a pivotal transcriptional activator of SIRT1 and consequently upregulates SIRT1 in the heart and potentially many other SIRT‐regulated physiological processes, which might protect the heart from I/R injury 19 . However, further experimental data found that HIC2 acts as a tumor suppressor gene and transcription repressor in glioma cells.…”

Proto-oncoprotein Zbtb7c and SIRT1 repression: implications in high-fat diet-induced and age-dependent obesity

“…The loss of HIC1 function promoted tumorigenesis by derepressing SIRT1 and thereby attenuated p53 function by deacetylation, which increases cancer risk in mammals 14 . Recently, we found that HIC2, a homolog to HIC1 with differing intermediate domains, is a transcriptional activator of SIRT1 and may protect the heart from ischemia/reperfusion (I/R) injury 15 .…”

“…The promoter-reporter fusion construct pGL2- SIRT1 -Luc and the expression vectors pcDNA3-FLAG- Zbtb7c , pcDNA3.1- Zbtb7c , pcDNA3- p53 , pcDNA3.1- HIC-1 , and pCMV- LacZ , in various combinations were transiently transfected into cells using Lipofectamine Plus reagent (Invitrogen, CA) and analyzed as described elsewhere 15 .…”

“…When DNA is damaged, HIC-1 and p53 jointly repress the SIRT1 gene by binding to two HIC-1REs and two p53REs, respectively 14 . Recently, HIC2 was shown to activate the transcription of SIRT1 15 . Zbtb7c, encoded by Zbtb7c , represses transcription by recruiting cofactor complexes (e.g., HDAC, NuRD, and BCoR complexes) 16 – 19 .…”

Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism

“…HIC family members include HIC1 and HIC2, with HIC2 the most greatly expressed in beta-cells (Extended Data Figure 8b). Interestingly, HIC2 is a transactivator of SIRT1 47 and the loss of SIRT1 impairs glucose sensing in beta-cells in mice 48 . Tier 2 disrupted motif families include TEAD and SMAD (Extended Data Figure 8c).…”