CNOT 1 cooperates with LMNA to aggravate osteosarcoma tumorigenesis through the Hedgehog signaling pathway

While treatments for childhood osteosarcoma have improved, the overall survival for this common type of bone cancer has not changed for three decades, and thus, new targets for therapeutic development are needed. To identify tumor‐related proteins in osteosarcoma, we used isobaric tags in a relative and absolute quantitation proteomic approach to analyze the differentially expressed proteins between osteosarcoma cells and human osteoblastic cells. Through clinical screening and functional evaluation, CCR4–NOT transcription complex subunit 1 ( CNOT 1) correlated with the growth of osteosarcoma cells. To date, the mechanisms and regulatory roles of CNOT 1 in tumors, including osteosarcoma, remain largely elusive. Here, we present evidence that knockdown of CNOT 1 inhibits the growth of osteosarcoma in vitro and in vivo . Mechanistically, we observed that CNOT 1 interacted with LMNA (lamin A) and functioned as a positive regulator of this intermediate filament protein. The RNA ‐seq analysis revealed that CNOT 1 depletion inhibited the Hedgehog signaling pathway in osteosarcoma cells. A rescue study showed that the decreased growth of osteosarcoma cells and inhibition of the Hedgehog signaling pathway by CNOT 1 depletion were reversed by LMNA overexpression, indicating that the activity of CNOT 1 was LMNA dependent. Notably, the CNOT 1 expression was significantly associated with tumor recurrence, Enneking stage, and poor survival in patients with osteosarcoma. Examination of clinical samples confirmed that CNOT 1 expression positively correlated with LMNA protein expression. Taken together, these results suggest that the CNOT 1– LMNA –Hedgehog signaling pathway axis exerts an oncogenic role in osteosarcoma progression, which could be a potential target for gene therapy.