RGS16 regulates Hippo-YAP activity to promote esophageal cancer cell proliferation and migration.

ABSTRACT

Esophageal Squamous Cell Carcinoma (ESCC) is a common malignant tumor of digestive tract, accounting for 90% of all pathological types of esophageal cancer. Despite the rapid development of multi-disciplinary treatment such as surgery, chemotherapy, radiotherapy and chemoradiotherapy, the prognosis of patients with ESCC is still poor. Regulators of G-protein signaling (RGSs) are involved in the processes of various cancers. The expression levels of its family member RGS16 are abnormally elevated in a variety of tumors, but its role in ESCC is still unclear. We found that RGS16 expression is aberrantly increased in ESCC tissues and correlated with poor prognosis of ESCC patients from The Cancer Genome Atlas (TCGA) database and our collected ESCC tissues. Moreover, knockdown of RGS16 in two ESCC cells could indeed inhibit their proliferation and migration. We further explored the molecular mechanism of RGS16 in ESCC, and the correlation analysis from TCGA database showed that the mRNA levels of RGS16 was positively correlated with that of CTGF and CYR61, two target genes of Hippo-YAP signaling. Consistently, RGS16- knockdown significantly inhibited the expression of CTGF and CYR61 in ESCC cells. We found that the phosphorylation levels of LATS1 and YAP were significantly increased and YAP translocated into the cytoplasm after depletion of RGS16 in ESCC cells. Also, RGS16-knockdown promoted the interaction between LATS1 and upstream kinase MST1. In addition, reintroduction of a constitutive active YAP5A mutant significantly rescued CTGF expression and cell proliferation in RGS16-knockdown cells. Together, our work revealed that RGS16 promoted YAP activity through disrupting the interaction between LATS1 and MST1, thus promoting the proliferation and migration of ESCC cells.