SEPT2 crotonylation promotes metastasis and recurrence in hepatocellular carcinoma and is associated with poor survival

Abstract

Background Hepatocellular carcinoma (HCC) metastasis and recurrence lead to therapy failure, which are closely associated with the proteome. However, the role of post-translational modification (PTM) in HCC, especially for the recently discovered lysine crotonylation (Kcr), is elusive. Results We investigated the correlation between crotonylation and HCC in 100 tumor tissues and performed stable isotope labeling by amino acids and liquid chromatography tandem mass spectrometry in HCC cells, and we found that crotonylation was positively correlated with HCC metastasis, and higher crotonylation in HCC cells facilitated cell invasiveness. Through bioinformatic analysis, we found that the crotonylated protein SEPT2 was significantly hypercrotonylated in highly invasive cells, while the decrotonylated mutation of SEPT2-K74 impaired SEPT2 GTPase activity and inhibited HCC metastasis in vitro and in vivo. Mechanistically, SIRT2 decrotonylated SEPT2, and P85α was found to be the downstream effector of SEPT2. Moreover, we identified that SEPT2-K74cr was correlated with poor prognosis and recurrence in HCC patients, thus indicating its clinical potential as an independent prognostic factor. Conclusions We revealed the role of nonhistone protein crotonylation in regulating HCC metastasis and invasion. Crotonylation facilitated cell invasion through the crotonylated SEPT2-K74-P85α-AKT pathway. High SEPT2-K74 crotonylation predicted poor prognosis and a high recurrence rate in HCC patients. Our study revealed a novel role of crotonylation in promoting HCC metastasis.

Large-scale identification of lysine crotonylation reveals its potential role in oral squamous cell carcinoma

“…Accumulating evidence has shown that proteins in human tumor tissues can be modi ed by crotonylation [22,23]. In several carcinoma types, including thyroid, esophagus, colon, pancreas, and lung, the global crotonylation was remarkably increased, while it was reduced in liver, stomach, and kidney carcinomas [24].…”

Large-Scale Identification of Lysine Crotonylation Reveals Its Potential Role in Oral Squamous Cell Carcinoma

“…Emerging evidence suggests that crotonylation can modulate protein function in human tumor tissues. 30 , 31 Global crotonylation levels have been found to be significantly increased in various carcinoma types, including thyroid, esophagus, colon, pancreas, and lung, while reduced in liver, stomach, and kidney carcinomas. 32 These observations indicate that crotonylation may play diverse roles in cancer progression by influencing distinct pathways.…”

A glimpse into novel acylations and their emerging role in regulating cancer metastasis

“…However, emerging evidence also highlights the positive relationship between novel acylation and HCC; it was documented that the Kcr of Septin 2 (SEPT2) promotes the invasion of HCC cells, with the SEPT2 in highly invasive HCC cells significantly hypercrotonylated; conversely, the K74 mutation of SEPT2 delayed its Kcr, leading to decreased GTPase activity of SEPT2 and impaired HCC metastasis in vitro and in vivo [ 142 ]. Previous research mentioned that mitochondrial transcription factor A (TFAM) downregulation in metastatic HCC induced Kma of mDia2 to promote its nuclear translocation and actin polymerization, thereby resulting in the high metastatic ability of HCC cells [ 143 ].…”