Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression

Abstract

Recently, studies on transcriptome-proteome relationships have revealed mRNA/protein expression discordance for certain genes and speculated that protein posttranslational modification (PTM) may be involved. However, there is currently no evidence to support this hypothesis. Wnt-induced secreted protein-1 (WISP1) is the downstream target gene of β-catenin and plays an important role in tumorigenesis and progression, but the expression and role of WISP1 in different tumor types are controversial. Here, we first confirmed that WISP1 protein expression was significantly down-regulated in hepatocellular carcinoma (HCC) tissue and could be an independent predictor of poor prognosis for patients with HCC. In vivo and in vitro evidence was provided that WISP1 can suppress HCC cell proliferation. Further studies have found that low WISP1 protein expression was related to expression of human leukocyte antigen F locus adjacent transcript 10 (FAT10), a specific ubiquitin-like protein with both degradation and stabilization functions, which plays an important role in PTM. FAT10 overexpression facilitated WISP1 degradation by FAT10ylation to decrease WISP1 protein expression, thus promoting HCC proliferation. Interestingly, we found and demonstrated that FAT10 overexpression could result in WISP1 protein/mRNA expression discordance, with protein expression decreasing while mRNA expression increased. The underlying mechanism is that FAT10 exerts substrate stabilization and degradation functions simultaneously, while FAT10 overexpression promotes WISP1 mRNA expression by stabilizing β-catenin and directly degrades WISP1 protein. Conclusion: Our study demonstrated that overexpression of FAT10 results in expression discordance between WISP1 protein and mRNA, thereby promoting HCC progression by down-regulating WISP1 protein expression.

UBA6 and Its Bispecific Pathways for Ubiquitin and FAT10

“…However, the over-expression of FAT10 resulted in a disorder of WISP1 mRNA and protein levels, with the expression of WISP1 protein decreasing and the mRNA expression of WISP1 increasing [80]. This study explained that FAT10 exerted its stabilization and degradation functions simultaneously by promoting WISP1 mRNA expression via stabilizing β-catenin yet directly targeting the WISP1 protein for degradation [80]. Nevertheless, there are converse results of FAT10ylation with tumor suppressor p53, whose reasoning remains unknown.…”

Activation of Adenosine Monophosphate—Activated Protein Kinase Reduces the Onset of Diet‐Induced Hepatocellular Carcinoma in Mice

“…(42) Among the discussed mechanisms is the subsequent degradation of WISP1 and modification of Wnt signaling. (43) We noticed decreased protein levels of WISP1 in the liver of AMLN-fed animals but did not detect a significant up-regulation of the protein in response to our AMPK activator. This could be due to the high variability of the biological material, because we worked with whole-liver homogenates.…”

Diagnostic Value of the Hypomethylation of the <i>WISP1</i> Promoter in Patients with Hepatocellular Carcinoma Associated with Hepatitis B Virus

“…Aberrant WISP1 expression is associated with multiple solid human tumors and plays a pivotal role in tumorigenesis and progression (Liu et al 2019). Studies have shown that WISP1 is linked to colon cancer, oral squamous cell carcinoma, gastric cancer, breast cancer, esophageal cancer, prostate cancer, hepatocellular carcinoma and so on (Nagai et al 2011;Ono et al 2013;Chiang et al 2015;Gurbuz and Chiquet-Ehrismann 2015;Clausen et al 2016;Wu et al 2016;Yan et al 2018;Loftus et al 2020;Zhang et al 2019). Clausen et al (2016) noticed that WISP1 expression was regulated by DNA methylation and that WISP1 demethylation contributed to lymph node metastasis in patients with oral squamous cell carcinoma.…”