SPTLC2 drives an EGFR-FAK-HBEGF signaling axis to promote ovarian cancer progression.

The epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with ovarian cancer (OC) progression. However, inhibition of EGFR signaling in OC patients achieved limited therapeutic effects, highlighting the need to define the mechanism of EGFR deregulation in OC development. Herein we showed that serine palmitoyltransferase long chain base subunit 2 (SPTLC2) acts as a positive regulator in the EGFR signaling pathway in OC. Phenotypically, depletion of SPTLC2 suppressed clonogenic growth and migration of OC cells in vitro and in ovo, as well as metastasis in OC xenograft models, whereas overexpression of SPTLC2 yielded opposite effects. Mechanistically, SPTLC2 drives an EGFR-FAK-HBEGF signaling axis via binding with EGFR. Notably, the serine palmitoyltransferase activity of SPTLC2 is critical for regulation of the EGFR-FAK-HBEGF signaling axis and activity in OC progression. Clinically, high SPTLC2 expression is associated with high-grade serous ovarian cancer and metastasis. Collectively, our findings establish an oncogenic role of SPTLC2 in OC growth and progression though upregulation of EGFR signaling and suggest that SPTLC2 represents a potential therapeutic target in EGFR-driven ovarian cancer patients.