De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy

Journal Article · Wed Sep 15 04:00:00 EDT 2021 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2021.112761· OSTI ID:23195533

Lu, Peng ^[1]; Xu, Yun ^[2]; Sheng, Zhi-yong ^[3]; Peng, Xiao-gang ^[4]; Zhang, Jing-jing ^[5]; Wu, Qing-hua; Wu, Yan-qing; Cheng, Xiao-shu; Zhu, Kai ^[1]

---

1. Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province (China)
2. Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province (China)
3. Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province (China)
4. Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province (China)
5. Graduate School of Nanchang University, Nanchang, 330006, Jiangxi Province (China)

Highlights: • The expression of USP12 is increased in Ang II-induced cardiac hypertrophy in vitro and in vivo. • USP12 aggravates Ang II-induced cardiomyocyte hypertrophy via upregulating METTL3. • USP12 promoted METTL3 expression via modulating p300. • USP12 suppresses the ubiquitination of p300 to block its degradation. Stresses, such as neurohumoral activation, induced pathological cardiac hypertrophy is the main risk factor for heart failure. The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is limited. Here, we observe that the deubiquitinating enzyme ubiquitin-specific protease 12(USP12) is upregulated in Ang II-induced hypertrophic hearts and primary neonatal rat cardiomyocytes (NRCMs). Inhibition of USP12 ameliorate Ang II-induced myocardial hypertrophy, while overexpression of USP12 have the opposite effect. USP12 deficiency also significantly attenuate the phenotype of Ang II-induced cardiac hypertrophy in vivo. Moreover, we demonstrate that USP12 aggravate Ang II-induced cardiac hypertrophy by enhancing METTL3, a methyltransferase which catalyze N{sup 6}-methyladenosine (m{sup 6}A) modification on messenger RNA and acts as a harmful factor in pathological cardiac hypertrophy. Upregulation of METTL3 reverse the reduction of myocardial hypertrophy induced by USP12 silencing in NRCMs. In contrast, knockdown of METTL3 attenuate the aggravation of myocardial hypertrophy in USP12-overexpressing NRCMs. Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300. Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3. Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy. Taken together, our results demonstrate that USP12 acts as a pro-hypertrophic deubiquitinating enzyme via enhancing p300/METTL3 axis, indicating that targeting USP12 could be a potential treatment strategy for pathological cardiac hypertrophy.

• OSTI ID: 23195533
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 406; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
HEART
HEART FAILURE
HOMEOSTASIS
HYPERTROPHY
IN VITRO
IN VIVO
INHIBITION
MESSENGER-RNA
METHYL TRANSFERASES
PHENOTYPE
RATS
TRANSCRIPTION