Deubiquitinase USP9x regulates the proline biosynthesis pathway in non-small cell lung cancer.
Tina BecirovicBoxi ZhangCecilia LindskogErik NorbergHelin Vakifahmetoglu-NorbergVitaliy O KaminskyyElena Y KochetkovaPublished in: Cell death discovery (2024)
Metabolic rewiring has been recognized as a hallmark of malignant transformation, supplying the biosynthetic and energetic demands for rapid cancer cell proliferation and tumor progression. A comprehensive understanding of the regulatory mechanisms governing these metabolic processes is still limited. Here, we identify the deubiquitinase ubiquitin-specific peptidase 9 X-linked (USP9x) as a positive regulator of the proline biosynthesis pathway in non-small cell lung cancer (NSCLC). Our findings demonstrate USP9x directly stabilizes pyrroline-5-carboxylate reductase 3 (PYCR3), a key enzyme in the proline cycle. Disruption of proline biosynthesis by either USP9x or PYCR3 knockdown influences the proline cycle leading to a decreased activity of the connected pentose phosphate pathway and mitochondrial respiration. We show that USP9x is elevated in human cancer tissues and its suppression impairs NSCLC growth in vitro and in vivo. Overall, our study uncovers a novel function of USP9x as a regulator of the proline biosynthesis pathway, which impacts lung cancer growth and progression, and implicates a new potential therapeutic avenue.
Keyphrases
- small cell lung cancer
- cell proliferation
- papillary thyroid
- transcription factor
- cell wall
- endothelial cells
- gene expression
- squamous cell
- small molecule
- advanced non small cell lung cancer
- squamous cell carcinoma
- lymph node metastasis
- long non coding rna
- quantum dots
- brain metastases
- pi k akt
- pluripotent stem cells