Regulation and targeting of SREBP-1 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic reprogramming. De novo lipogenesis is under the control of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1) and essentially contributes to HCC progression. Here, we summarize the current knowledge on the regulation of SREBP-1 isoforms in HCC based on cellular, animal, and clinical data. Specifically, we (i) address the overarching mechanisms for regulating SREBP-1 transcription, proteolytic processing, nuclear stability, and transactivation and (ii) critically discuss their impact on HCC, taking into account (iii) insights from pharmacological approaches. Emphasis is placed on cross-talk with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) axis, AMP-activated protein kinase (AMPK), protein kinase A (PKA), and other kinases that directly phosphorylate SREBP-1; transcription factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), proliferator-activated receptor γ co-activator 1 (PGC-1), signal transducers and activators of transcription (STATs), and Myc; epigenetic mechanisms; post-translational modifications of SREBP-1; and SREBP-1-regulatory metabolites such as oxysterols and polyunsaturated fatty acids. By carefully scrutinizing the role of SREBP-1 in HCC development, progression, metastasis, and therapy resistance, we shed light on the potential of SREBP-1-targeting strategies in HCC prevention and treatment.

Keywords: Cancer; Fatty acids; Ferroptosis; Lipogenesis; Mode of action; Pharmacotherapy.

Fig. 1

Proteolytic processing of SREBP-1 stimulates de novo lipogenesis and sustains tumorigenesis. pSREBP binds to SCAP and is anchored to the ER membrane by Insigs. Under low cellular sterol conditions, the SCAP-SREBP complex is released from Insigs and transferred to the Golgi, where pSREBP is cleaved by S1P and S2P, releasing the soluble mSREBP into the cytosol. mSREBP forms homodimers and translocates to the nucleus, binds to promoters with SREs or E-boxes, and transactivates the transcription of target genes. By inducing the expression of lipogenic enzymes (ACLY, ACC, FASN, elongation of long fatty acids family member 6 (ELOVL6), and SCD shown in purple) and enhancing de novo lipogenesis, SREBP-1 promotes membrane biogenesis, which is essential for tumor growth. Figure modified from Horton et al. and Moon et al. [16, 25] and created with https://www.biorender.com/

Fig. 2

Regulation of SREBP-1 in HCC. Focus is placed on the canonical pathways that link major regulators of SREBP-1 signaling to either SREBP-1 transcription, SREBP-1 mRNA stability, pSREBP-1 maturation and intracellular trafficking, mSREBP-1 post-translational modification affecting protein stability, degradation, and transactivating activity. Major regulatory pathways that coordinate the SREBP-1 signaling include (i) the PI3K-Akt-mTOR axis, thereby considering links to lipin-1, CRTC2, TIP30, and other PI3K-Akt-regulated pathways; (ii) the serine kinases AMPK and PKA as well as other kinases that directly phosphorylate SREBP-1; (iii) the transcription factors LXR, PPARs, STAT, Myc, and p53; (iv) histone acetyltransferases, sirtuins, PRMT5, and other factors that control post-translational modification of SREBP-1; (v) metabolites, including PUFAs; and (vi) various other regulatory factors and mechanisms, such as the microRNA miR-27a, the RNA binding proteins Lin28A and Lin28B, and nuclear-localized HDGF. Created with https://www.biorender.com/