14‐3‐3ζ binds to and stabilizes phospho‐beclin 1^S295 and induces autophagy in hepatocellular carcinoma cells

Abstract

Data from The Cancer Genome Atlas (TCGA) indicate that the expression levels of 14‐3‐3ζ and beclin 1 (a key molecule involved in cellular autophagy) are up‐regulated and positively correlated with each other (R = .5, P < .05) in HCC tissues. Chemoresistance developed in hepatoma cancer cells is associated with autophagy initiation. This study aimed to explore 14‐3‐3ζ’s role in regulating autophagy in HCC cells, with a focus on beclin 1. The co‐localization of 14‐3‐3ζ and beclin 1 was detectable in primary HCC tissues. To simulate in vivo tumour microenvironment (hypoxia), CSQT‐2 and HCC‐LM3 cells were exposed to 2% oxygen for 24 hours. The protein levels of 14‐3‐3ζ and phospho‐beclin 1S295 peaked at 12 hours following hypoxia. Meanwhile, the strongest autophagy flux occurred: LC3II was increased, and p62 was decreased significantly. By sequencing the coding area of BECN 1 gene of CSQT‐2 and HCC‐LM3 cells, we found that the predicted translational products of BECN 1 gene contained RLPS295VP (R, arginine; L, leucine; P, proline; S, serine; V, valine), a classic 14‐3‐3ζ binding motif. CO‐IP results confirmed that 14‐3‐3ζ bound to beclin 1, and this connection was markedly weakened when S295 was mutated into A295 (alanine). Further, 14‐3‐3ζ overexpression prevented phospho‐beclin 1S295 from degradation and enhanced its binding to VPS34, whilst its knockdown accelerated the degradation. Additionally, 14‐3‐3ζ enhanced the chemoresistance of HCC cells to cis‐diammined dichloridoplatium by activating autophagy. Our work reveals that 14‐3‐3ζ binds to and stabilizes phospho‐beclin 1S295 and induces autophagy in HCC cells to resist chemotherapy.

[Retracted] Overexpression of 14‐3‐3δ Predicts Poor Prognosis in Extrahepatic Cholangiocarcinoma Patients

“…Elevated expression of 14-3-3 δ protein have been reported recently in head and neck squamous cell carcinomas [ 10 ], liver cancer [ 11 ], nonsmall cell lung cancer, colorectal carcinoma [ 12 ], and breast cancer [ 13 ]. In our previous study, we also found the level of 14-3-3 δ protein is elevated in cholangiocarcinoma, but the samples contained a large portion of intrahepatic CCA [ 14 ], the role and expression of 14-3-3 δ in the development of extrahepatic CCA has not been well studied so far.…”

A hypoxia-linked gene signature for prognosis prediction and evaluating the immune microenvironment in patients with hepatocellular carcinoma

“…Understanding the HCC immune microenvironment will improve the development of immunotherapies. Interestingly, increasing evidence suggests that hypoxia affects components of the HCC immune microenvironment (23)(24)(25). Therefore, investigating the gene expression changes associated with hypoxia pathways might contribute to survival benefits for patients with HCC.…”

The Roles of Beclin 1 Expression in Gastric Cancer: A Marker for Carcinogenesis, Aggressive Behaviors and Favorable Prognosis, and a Target of Gene Therapy

“…RNF216 interacts with and ubiquitinates Beclin 1 at lysine 48, thereby contributing to Beclin 1 degradation, while SLC9A3R1 and USP19 blocks ubiquitin-dependent Beclin 1 degradation by interacting with Beclin 1 and removing the K11-linked ubiquitin respectively (9, 10). Liu et al (11) found that Beclin 1, the core molecule of the Becn1-PIK3C3 complex, could be SUMO3-conjugated by PIAS3 predominantly at K380 and deSUMOylated by SENP3. Tang et al (12) reported that 14-3-3z bound to and stabilized phospho-Beclin 1(S295), and induced autophagy and chemoresistance in hepatocellular carcinoma cells.…”

“…Liu et al. ( 11 ) found that Beclin 1, the core molecule of the Becn1-PIK3C3 complex, could be SUMO3-conjugated by PIAS3 predominantly at K380 and deSUMOylated by SENP3. Tang et al.…”