HDCA6 suppresses GATA6 expression to enhance cellular growth and migration in lung squamous cell carcinoma

Background: Lung squamous cell carcinoma (LUSC) exhibits a significant mortality rate and lacks effective targeted therapies. The GATA-binding factor 6 (GATA6), a pivotal regulator of lung development, undergoes reduced expression in LUSC and correlates with its metastasis and prognosis. However, the regulatory mechanisms underlying the down-regulation of GATA6 in LUSC remain elusive. HDAC6 emerges as a promising therapeutic target in preclinical Cancer models. Nevertheless, its role in LUSC progression remains unexplored. Furthermore, the regulatory impact of HDAC6 on GATA6 expression needs clarification. The purpose of this work is to investigate HDAC6's involvement and regulatory mechanisms on the expression of GATA6 in LUSC.

Methods: The impacts of HDCA6 on the expression of GATA6 were assessed using qPCR, Western blot and CHIP assays. The tumorigenic capacity of HDAC6 in promoting the growth and migration of LUSC cell were determined through CCK8, EdU incorporation, Transwell, and xenograft tumor models. Immunohistochemistry assays were employed to detected expression of HDAC6 in tissue microarray of LUSC.

Results: A pan-HDACs inhibitor Trichostatin A and an HDAC6-specific inhibitor CAY10603 up-regulate the expression of GATA6, whereas HDAC6 overexpression down-regulates GATA6 level. Overexpression of HDAC6 promotes cell proliferation and migration in LUSC, while inhibition of HDAC6 significantly suppresses LUSC cell growth. And, GATA6 overexpression reverses HDAC6-mediated elevated growth and migration of LUSC cells. Compared to normal tissues, LUSC tissues exhibit elevated levels of HDAC6 expression, which were correlated with poor prognosis of LUSC patients.

Conclusion: Targeting HDAC6/GATA6 pathway may offer promising prospects for developing of novel therapeutic strategies against LUSC.

GATA6; HDAC6; LUSC; Migration; Proliferation.