TFE3 and HIF1a regulates the expression of SHMT2 isoforms via alternative promoter utilization in ovarian cancer cells

Ovarian cancer ranks first lethally among gynecological malignancies. Platinum-based chemotherapy constitutes the first-line therapeutic regime. However, primary or acquired resistance seriously affects the survival rate of patients with ovarian cancer. Serine hydroxy methyltransferase (SHMT) catalyzes conversion of serine to glycine and is responsible for production of S-adenosylmethionine (SAM) for methylation. There are cytosolic SHMT1 and mitochondrial SHMT2 in human. Alternative promoter usage is a proteome-expanding mechanism that allows multiple pre-mRNAs to be transcribed from a single gene. The current study demonstrated that cisplatin-sensitive and cisplatin-resistant ovarian cancer cells expressed discrete SHMT2 isoforms, which was ascribed to the selective utilization of SHMT2 alternative promoters. SHMT2 isoforms exerted somewhat paradoxical roles in ovarian cancer cells, with tumor-suppressive role of isoform 1, and tumor-promotive role of isoform 3. In addition, the current study demonstrated that SHMT2 alternative promoter usage mediated by HIF1α and TFE3 might represent adaptive response of ovarian cancer cells to metabolic stress. Collectively, regulation of SHMT2 isoform expression via alternative promoter usage by transcription factors HIF1α and TFE3 provides a novel basis and potential drug targets for the clinical treatment of platin-resistant ovarian cancer.