Aberrant transcriptional and post-transcriptional regulation of SPAG5, a YAP-TAZ-TEAD downstream effector, fuels breast cancer cell proliferation

Abstract

Sperm-associated antigen 5 (SPAG5) is an important driver of the cell mitotic spindle required for chromosome segregation and progression into anaphase. SPAG5 has been identified as an important proliferation marker and chemotherapy-sensitivity predictor, especially in estrogen receptor-negative breast cancer subtypes. Here, we report that SPAG5 is a direct target of miR-10b-3p, and its aberrantly high expression associates with poor disease-free survival in two large cohorts of breast cancer patients. SPAG5 depletion strongly impaired cancer cell cycle progression, proliferation, and migration. Interestingly, high expression of SPAG5 pairs with a YAP/TAZ-activated signature in breast cancer patients. Reassuringly, the depletion of YAP, TAZ, and TEAD strongly reduced SPAG5 expression and diminished its oncogenic effects. YAP, TAZ coactivators, and TEAD transcription factors are key components of the Hippo signaling pathway involved in tumor initiation, progression, and metastasis. Furthermore, we report that SPAG5 is a direct transcriptional target of TEAD/YAP/TAZ, and pharmacological targeting of YAP and TAZ severely reduces SPAG5 expression. Collectively, our data uncover an oncogenic feedback loop, comprising miR-10b-3p, SPAG5, and YAP/TAZ/TEAD, which fuels the aberrant proliferation of breast cancer.

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

“…The complex is then responsible for cell proliferation and transformation. Abnormal nuclear expression of YAP/TAZ proteins is associated with poor prognosis of different types of cancer [ 11 , 12 , 13 , 14 , 15 ]. In addition, YAP/TAZ can associate with other transcription factors leading to cell remodelling, proliferation, and invasion [ 16 ].…”

Identification of Tissue-Specific Expressed Hub Genes and Potential Drugs in Rheumatoid Arthritis Using Bioinformatics Analysis

“…SPAG5 is a Protein Coding gene involved in the functional and dynamic regulation of mitotic spindles. There is growing evidence that it is upregulated in many human cancers, acting as an oncogene and promoting cell proliferation (Liu et al, 2018;He et al, 2020;Canu et al, 2021). CUX2 is a Protein Coding gene encoding a transcription factor which contains three CUT domains and a homeodomain.…”

Comprehensive analysis of SPAG1 expression as a prognostic and predictive biomarker in acute myeloid leukemia by integrative bioinformatics and clinical validation

“…SPAG4 could act as a potential biomarker of glioblastoma progression and prognosis, as well as in renal cell carcinoma and lung carcinoma [ 21 – 23 ]. Moreover, SPAG5 hyperexpression was connected to poor disease-free survival in breast cancer patients, and fueled breast cancer cell proliferation [ 24 ]. Interestingly, reduced expression of SPAG6 , which is transcriptionally regulated by tumor specific DNA methylation, has been revealed in non-small-cell lung cancer [ 25 ].…”