Acetylation drives hepatocyte nuclear factor 1β stability by blocking proteasome‐mediated degradation

• Published in: Journal of cellular biochemistry 2019-06, Vol.120 (6), p.9337-9344
• Main Authors: Lopes‐Coelho, Filipa, Silva, Fernanda, Hipólito, Ana, Cardoso, Bruno A., Serpa, Jacinta
• Format: Article
• Language: English
• Subjects: Acetylation; Carcinoma; Chromatin; Degradation; Gene expression; Genitourinary tract; Hepatocellular carcinoma; hepatocyte nuclear factor 1β (HNF1β); histone deacetylase inhibitor (HDACi); Homeobox; Kidneys; Liver; Organs; Pancreas; Proteasomes; protein turnover; Proteins; Stability; Stabilization; Transcription factors; Tumor suppressor genes; Ubiquitin; ubiquitin‐proteasome system
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.28209

Hepatocyte nuclear factor 1β (HNF1β) is mostly expressed in the liver, but is also expressed in other organs, like kidney, pancreas and genitourinary tract. In fact, HNF1β, a member of the superfamily of homeodomain‐containing transcription factors, has been described as a hallmark in clear cell carcinomas. However, its role as an oncogene or as tumor suppressor gene remains controversial. Here, we disclose a mechanism of HNF1β stabilization and degradation, using human HNF1β‐expressing cell lines of ovarian clear cell carcinoma (ES2), hepatocellular carcinoma (HEPG2), and normal immortalized kidney tubular cells (HK2). We show that increased levels of HNF1β is concomitant with an increase in the acetylation load and protein stabilization by interfering with the ubiquitin‐proteasome degradation system. This study reinforces that acetylation, besides their role in regulating chromatin conformation and gene expression, could also act in the action, turnover and stability of proteins essential for the survival and progression of certain cancer types. In this report, we described for the first time that hepatocyte nuclear factor 1β (HNF1β) is regulated at a posttranslational level by acetylation. Moreover, this cellular mechanism could constitute a mechanism of modulation and/or activation of HNF1β. Our study opens new perspectives for a better understanding of HNF1β function and their role as a tumor suppressor protein or as an oncoprotein. We believe that the two scenarios can be possible depending on the context and on the mutational status of HNF1B gene. These evidence reinforce the fact that each tumor is an entity and must be specific and particularly studied to provide a proper treatment of each patient with cancer.