RNF12 is regulated by AKT phosphorylation and promotes TGF-β driven breast cancer metastasis

Abstract

Transforming growth factor-β (TGF-β) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-β signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-β and AKT signaling pathways during breast cancer progression.

Ring finger protein 12 activates AKT signalling to promote the progression of liver cancer by interacting with EGFR

“…29 RNF12, as a member of the ring finger protein family, has been reported to be dysregulated in many malignancies. 12,13,30 RNF12 was reported to be overexpressed in glioblastoma, which was correlated with a poor prognosis. 13 Furthermore, RNF12 was found to interact with and target RB1 for degradation to stimulate the MAPK pathway and promote the malignant proliferation of glioblastoma.…”

“…Physiologically, RNF12 has been reported to be involved in the inactivation of X chromosome, embryonic development, cell differentiation and maintenance of neural function 11 . Recently, increasing research showed that RNF12 was involved in the development of cancer 12 . In glioblastoma, RNF12 was reported to be highly expressed and related to poor prognosis of patients 13 .…”

“…Meantime, RNF12 interacted with and ubiquitinated RB1 to induce its degradation, which activated the MAPK signalling pathway to promote the proliferation of glioblastoma 13 . In breast cancer, the high expression of RNF12 was reported to be related to the distant metastasis of breast cancer patients 12 . In addition, RNF12 interacted with and ubiquitinated SMAD7 to cause its degradation and promote TGF‐β‐induced breast cancer metastasis 12 .…”

“…In breast cancer, the high expression of RNF12 was reported to be related to the distant metastasis of breast cancer patients 12 . In addition, RNF12 interacted with and ubiquitinated SMAD7 to cause its degradation and promote TGF‐β‐induced breast cancer metastasis 12 . However, RNF12 interacted with c‐myc and decreased its transcriptional activity to inhibit the cellular proliferation of osteosarcoma cells 14 .…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“…For example, AKT promotes TGF‐β‐driven breast cancer metastasis by mediating RNF12 phosphorylation and enhancing RNF12 stability. 177 KNSTRN, a component of the mitotic spindle, phosphorylates AKT at Thr308 and Ser473 to activate AKT and promote bladder cancer metastasis. 178 TKT, a key metabolic enzyme in the pentose phosphate pathway (PPP), interacts with GRP78 to promote glycolysis by increasing AKT phosphorylation, which promotes CRC metastasis.…”