The constitutive photomorphogenic 9 (
COP9) signalosome complex subunit 6 (COPS6/CSN6) is crucial for structural integrity of the
COP9 signalosome complex. CSN6 participates in various aspects of
cancer progression, but its role in
hypertrophic cardiomyopathy is not clear. Here, we found that the expression of CSN6 was increased in
Angiotensin II (Ang II)-induced hypertrophic mice hearts and neonatal rat cardiomyocytes (NRCMs). Inhibition of CSN6 decreased the cardiomyocyte size and fetal genes' expression in Ang II-induced hypertrophic NRCMs, while overexpression of CSN6 aggravated Ang II-induced myocardial
hypertrophy. Moreover, we demonstrated that the pro-hypertrophic function of CSN6 was mediated by
SIRT2, which acts as a cardioprotective factor in pathological
cardiac hypertrophy. CSN6 inhibited the expression of
SIRT2, and re-expression of
SIRT2 attenuated the myocardial
hypertrophy caused by CSN6 overexpression. Further investigation discovered that CSN6 suppressed the expression of
SIRT2 via up-regulating Nkx2.2, a transcription suppressor of
SIRT2. Mechanistically, CSN6 blocked the
ubiquitin proteasome system-mediated degradation of
Nkx2.2 protein by interacting with it and inhibiting its ubiquitination directly in cardiomyocytes. Finally, our data showed that CSN6 was partially dependent on the stabilization of
Nkx2.2 protein to inhibit
SIRT2 and promote myocardial
hypertrophy. Overall, our study identified CSN6 as a pro-hypertrophic
deubiquitinase, and CSN6 inhibition may be a potential treatment strategy for
heart failure.