Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway

Abstract

Intrinsic resistance to CDK4/6 inhibitors hinders their clinical utility in cancer treatment. Furthermore, the predictive markers of CDK4/6 inhibitors in gastric cancer (GC) remain incompletely described. Here, we found that PAX6 expression was negatively correlated with the response to palbociclib in vitro and in vivo in GC. We observed that the PAX6 expression level was negatively correlated with the overall survival of GC patients and further showed that PAX6 can promote GC cell proliferation and the cell cycle. The cell cycle is regulated by the interaction of cyclins with their partner serine/threonine cyclin‐dependent kinases (CDKs), and the G1/S‐phase transition is the main target of CDK4/6 inhibitors. Therefore, we tested whether PAX6 expression was correlated with the GC response to palbociclib. We found that PAX6 hypermethylates the promoter of LATS2 and inactivates the Hippo pathway, which upregulates cyclin D1 (CCND1) expression. This results in a suppressed response to palbociclib in GC. Furthermore, we found that the induction of the Hippo signaling pathway or treatment with a DNA methylation inhibitor could overcome PAX6‐induced palbociclib resistance in GC. These findings uncover a tumor promoter function of PAX6 in GC and establish overexpressed PAX6 as a mechanism of resistance to palbociclib.

DNA Topoisomerase II-α Regulated by miR-22-5p Promotes Hepatocellular Carcinoma Invasion and Migration through the Hippo Pathway

“…Hippo Signaling Pathway. Oncogenes often promote tumor progression by regulating the signaling pathways [12,13]. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that TOP2A was associated to cell cycle, progesterone-mediated oocyte maturation, p53 signaling pathway, and Hippo signaling pathway (Figure 5(a)).…”

“…Dysregulation of the Hippo signaling pathway promotes cancer progression [ 12 , 13 ]. Moya et al [ 14 ] found that the activity of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in tumors was linked to the progression of liver tumors.…”

hsa_circ_0067514 suppresses gastric cancer progression and glycolysis via miR-654-3p/LATS2 axis

“…In breast cancer, LATS2 12 suppresses cancer progression through maintaining cell identity and metabolic state [41]. LATS2 also participates in gastric cancer proliferation and invasion [42,43]. This study found that LATS2 was down-regulated in gastric cancer.…”

Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1

“…It plays a critical role in centrosome duplication, mitotic delity, and genomic stability, and negatively regulates the G1/S transition by reducing cyclin E/CDK2 kinase activity. Here, we found dysregulation of Hippo after depletion of LEF1 and KDM4A, and noticed that LATS2 regulated multiple downstream targets associated with cell cycle and apoptosis [48,49]. After knockdown of LEF1 or KDM4A, the cell cycle was stalled at the G1 phase [17,50], which may be due to the increased level of LATS2.…”