Tumor suppressor ZHX2 inhibits NAFLD–HCC progression via blocking LPL-mediated lipid uptake

Abstract

Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD-HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD-HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.

ZHX2 inhibits SREBP1c‐mediated de novo lipogenesis in hepatocellular carcinoma via miR‐24‐3p

“…ZHX2 not only inhibits transcription of AFP and GPC3 in HCC [19][20][21] but also down-regulates cyclin A and cyclin E to reduce cell proliferation, and MDR1 to enhance the chemo-sensitivity of HCC [21,22]. Together with other data, our data suggest lipid reprograming as a new mechanism for ZHX2-mediated HCC suppression [15,16,24]. A recent study showed that a…”

“…This result indicated that ZHX2 plays an important role in the development of NAFLD, which is an independent risk factor for HCC [3–5]. Similarly, our recent research showed that ZHX2 transcriptionally repressed expression of LPL, led to a decrease of exogenous lipid uptake, and retarded the progression of NAFLD‐HCC [15]. In addition to exogenous lipids, DNL was increased in many tumor biological processes, including promoting cell proliferation and metastasis, and enhancing chemoresistance [8,9,33].…”

“…ZHX2 (zinc fingers and homeoboxes 2), a transcriptional repressor, is a member of the ZHX family [14]. Growing evidence has demonstrated the critical involvement of ZHX2 in liver carcinogenesis as well as lipid homeostasis [15,16]. ZHX2 is responsible for postnatal repression of the oncofetal proteins alpha‐fetoprotein (AFP), glypican‐3 (GPC3), and long non‐coding RNA H19 in mice [17,18].…”

“…Recently, we reported a role for ZHX2 in hepatic lipid homeostasis. ZHX2 inhibits LPL‐mediated exogenous lipid uptake in hepatocytes, leading to retardation in NAFLD and consequent HCC [15]. However, whether ZHX2 is involved in DNL remains largely unknown.…”

ZHX2 drives cell growth and migration via activating MEK/ERK signal and induces Sunitinib resistance by regulating the autophagy in clear cell Renal Cell Carcinoma

“…Yue et al 27 also discovered that ZHX2 inhibited the growth of HCC cell lines by transcriptional represses of two key cell cycle regulators, Cyclin A and Cyclin E 27 . Later, Wu et al 28 reported ZHX2 could protect hepatocytes from lipid deposition disorder in non-alcoholic fatty liver disease to retard cell growth and its-related HCC progression. All these researches illustrated that in the process of disease and tumorigenesis, ZHX2 usually played the role of tumor suppressor gene.…”