Matrix stiffness drives HCC invasion and metastasis via interfering with TRIM21-mediated SCD1 ubiquitination.

Matrix stiffness drives the invasion and metastasis of hepatocellular carcinoma (HCC), wherein stearoyl-CoA desaturase 1 (SCD1), as a bona fide functional downstream effector of matrix stiffness, mediates HCC cell invasion and metastasis. However, the regulatory mechanism of SCD1 in response to matrix stiffness remains elusive. In this study, we identified a novel mechanism whereby F-actin cytoskeletal stress fiber assembly, triggered by increased matrix stiffness, sequesters the SCD1-targeting E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21), resulting in reduced proteasomal degradation of SCD1 and consequently increased SCD1 protein levels, leading to HCC cell invasion and metastasis. When HCC cells were plated on soft substrates, a significant downregulation of HCC cell invasion was observed, a condition under which F-actin stress fiber disassembly released the SCD1-targeting TRIM21, leading to accelerated SCD1 proteasomal degradation and decreased SCD1 protein levels. Mechanistically, TRIM21 catalyzes K48-linked ubiquitination of SCD1 at lysine 68 (K68), resulting in proteasome-dependent degradation of SCD1, a process modulated by matrix stiffness. Genetic overexpression of TRIM21 suppresses HCC invasion and metastasis in vivo. In human HCC samples, increased collagen I content (a surrogate marker of matrix stiffness) together with TRIM21/F-actin co-localization predicted poor survival in HCC patients. Our findings reveal a new mechanotransduction pathway involving F-actin cytoskeleton stress fiber (dis)assembly, TRIM21, and SCD1 that responds to matrix stiffness mechanical signals from the tumor microenvironment to drive HCC invasion and metastasis.