KDM5B regulates the PTEN/PI3K/Akt pathway to increase sorafenib-resistance in hepatocellular carcinoma

Abstract

Lysine-specific demethylase 5B (KDM5B) exerts its tumor-promoting functions in numerous malignancies, although the possible mechanisms by which KDM5B promotes cancer aggressiveness in hepatocellular carcinoma (HCC) have been preliminarily explored, the role of this gene in regulating sorafenib-resistance in HCC has not been studied. Thus, the present study was designed to resolve this problem, and our data suggested that KDM5B was significantly upregulated in the HCC tissues collected from patients with sorafenib treatment history. Consistently, continuous low-dose sorafenib administration increased KDM5B expression levels in the sorafenib-resistant HCC cells compared to their sorafenib-sensitive counterparts. Next, by performing the functional experiments, we found that KDM5B positively regulated sorafenib-resistance and cancer stem cell (CSC) properties in HCC cells in vitro and in vivo. Furthermore, upregulation of KDM5B-degraded phosphatase and tensin homolog (PTEN), results in the activation of the downstream oncogenic PI3K/Akt pathway. Subsequently, the rescuing experiments verified that the promoting effects of KDM5B overexpression on chemoresistance and cancer stemness in HCC cells were all abrogated by PI3K (p110) knockdown and PTEN overexpression. Collectively, those data hinted that KDM5B influenced CSC properties and sorafenib-resistance in HCC cells through modulating the PTEN/PI3K/Akt pathway, and KDM5B could be used as a potential target for the treatment of HCC in clinic.

[Retracted] KDOAM‐25 Overcomes Resistance to MEK Inhibitors by Targeting KDM5B in Uveal Melanoma

“…Our study showed that KDOAM-25 overcomes the MEK resistance by targeting KDM5B in UM. In a recent study, KDM5B regulates the PTEN/PI3K/Akt pathway to increase sorafenib resistance in hepatocellular carcinoma [ 30 ]. Also, one possible explanation resides in the fact that the small compound KDOAM-25 may eventually be inhibiting the expression of KDM5B, resulting in the upregulation of H3K4me3 and H3K27ac, consequently leading to the sensitivity to the MEK inhibitor in UM.…”

The role and prospect of lysine‐specific demethylases in cancer chemoresistance

“…Protein kinase B (AKT) is a significant downstream effecter of phosphatidylinositol 3‐kinase (PI3K) signaling which directs intracellular signal cascades 171,172 . The PI3K/AKT pathway is a key link that promotes the multidrug resistance of cancers via modulating several pathways, including inhibition of apoptosis, suppression of ferroptosis, and promoting cancer stemness 100,172,173 . It was shown that KDM5B downregulated PTEN, a classic tumor suppressor in many cancers, and activated the PI3K/Akt pathway to promote cancer stemness 100 .…”

“…171,172 The PI3K/AKT pathway is a key link that promotes the multidrug resistance of cancers via modulating several pathways, including inhibition of apoptosis, suppression of ferroptosis, and promoting cancer stemness. 100,172,173 It was shown that KDM5B downregulated PTEN, a classic tumor suppressor in many cancers, and activated the PI3K/Akt pathway to promote cancer stemness. 100 Chen et al 174 reported that EZH2 suppresses the expression of IGFBP5, which increases radiosensitivity of prostate cancer cells through the PI3K-AKT pathway.…”

“…100,172,173 It was shown that KDM5B downregulated PTEN, a classic tumor suppressor in many cancers, and activated the PI3K/Akt pathway to promote cancer stemness. 100 Chen et al 174 reported that EZH2 suppresses the expression of IGFBP5, which increases radiosensitivity of prostate cancer cells through the PI3K-AKT pathway. KDM6B counteracts EZH2-mediated suppression of IGFBP5 and confers breast cancer cell resistance to PI3K/AKT inhibitors.…”

Lysine demethylase 5B (KDM5B): A key regulator of cancer drug resistance

“…As shown in Schema 5, Nie and colleagues found that high expression of KDM5B can promote the drug resistance of hepatoma cells to sorafenib; And they found that KDM5B can activate the PI3K/AKT pathway, which can increase the expression level of pro‐stemness biomarkers, including CD133, CD44, and EpCAM, to promote CSC properties. [ 101 ] As is well known, the PI3K/AKT pathway plays an important role in the occurrence and development of various cancers, and CSCs can promote the resistance of various cancer cells to various chemical drugs. This study provides an important theoretical basis for KDM5B in the treatment of chemotherapy resistance.…”