Table 1.
The roles and molecular mechanisms of the SREBP-2-regulated mevalonate pathway in different cancers.
| Cancer type | Targets | Molecular mechanism from the findings |
|---|---|---|
| Prostate cancer | SREBP-1, SREBP-2, HMGCS, HMGCR, FPPS | Androgen induces the activation of SREBPs and the expression of multiple enzyme genes, including HMGCS, HMGCR and FPPS in normal physiological conditions and steroid-regulated cancers (74, 96) |
| SCAP, INSIG | Androgen stimulates SCAP expression and causes a switch in INSIG isoform for lipogenesis (73, 97) | |
| SREBP-2 | Induced by a 3-fold increase during the progression to androgen independence (90) | |
| SREBP-2 | Elevated in advanced pathologic grade and metastasis of prostate cancer and significantly associated with poor clinical outcomes (14) | |
| SREBP-2 | Promotes cancer cell growth, stemness and metastasis through transcriptional c-Myc activation (14) | |
| HMGCS1, HMGCR | Overexpressed in stroma of early stage PCa (101) | |
| HMGCR | Elevated in enzalutamide-resistant cancer and more sensitive to statins (102) | |
| FPPS | Associated with increasing Gleason score and poor survival through modulation of small GTPase/Akt axis (103, 104) | |
| SQS | The allele at rs2645429 is significantly associated with cancer risk and aggressive phenotypes (105) | |
| Breast cancer | SREBP-2 | CtBP can form a complex with ZEB1 to transcriptionally repress SREBP-2 expression and activate TGF-β signaling (106) |
| SREBP-2, HMGCR, FPPS, SQS, DHCR7 | TP53 mutation upregulates with the mevalonate pathway genes, HMGCR, FPPS, SQS, and DHCR7 through interaction with SREBP-2 (20) | |
| SREBPs | PI3K or K-Ras can induce mTORC1 signaling to promote cancer growth through SREBP-2 or SREBP-1 activation (107) | |
| SREBP-2 | Highly expressed in cancer tissues and correlated with a poor prognosis (15) | |
| SREBP-2 | Increased during the early stages of osteoclast formation under the control of the RANKL/cAMP-CREB signaling and induced the expressions of NFATc1 and matrix metalloproteinases for cancer-induced osteolysis (15) | |
| HMGCR | Correlated with the cancer risk and poor survival (111–113) | |
| Cholesterol | Implicated as a cancer, tumor growth and metastasis risk factor (114) | |
| 27-hydroxycholesterol | Increases the proliferation of estrogen receptor (ER)-positive breast cancer through the activation of ER and LXR (115) | |
| Lung cancer | HMGCR | The allele at rs12916 is significantly associated with the attained age for cancer patients (111) |
| SQS | The allele at rs2645429 is a risk factor for non-small cell lung cancer (NSCLC) (116) | |
| SQS | Associated with the metastasis and poor prognosis by regulating NF-κB-mediated the up-regulation of matrix metallopeptidase-1 or extracellular signal-regulated kinase signaling (117, 120) | |
| FPPS | Promotes cell invasion and epithelial mesenchymal transition (EMT) through the RhoA/ROCK1 pathway (118) | |
| GGPPSS | Increases cancer invasion and migration by regulating EMT (119) | |
| Hepatocellular carcinoma | SREBP-2 | p53 induces the accumulation and stabilization of mature SREBP-2 by transcriptional ABCA1 induction (21) |
| SREBP-2 | ASPP2, a p53 activator interacts with SREBP-2 in the nucleus to negatively affect the mevalonate pathway (122) | |
| SREBP-2 | Staphylococcal nuclease and tudor domain containing-1 (SND-1) results in the accumulation of cholesteryl esters through the activation of SREBP-2 (123) | |
| SREBP-2 | Binds to specific sites in SND-1 promoter to contribute lipid metabolism reprogramming (91) | |
| SREBP-2, HMGCR | Fatty acid synthase ablation promotes nuclear localization of SREBP-2 and increases HMGCR expression to maintain carcinogenesis (124) | |
| SREBP-2, HMGCR | Forkhead Box M1 has a positive correlation with SREBP-2 or HMGCR in hepatocellular carcinoma through protein geranylgeranylation (125) | |
| Esophageal squamous cell carcinoma | SREBP-2 | Promotes cell growth, migration and colony formation through interaction with c-Myc; SREBP-2 is upregulated in clinical samples (16) |
| Renal carcinoma | SREBP-2 | Kruppel-like factor 6 activates mTOR-SREBP-2 to enhance tumor growth (126) |
| Pancreatic cancer | SREBP-2 | Small nucleolar RNA host gene 16 directly regulates the miR-195/SREBP-2 axis to promote cancer progression (127) |
| Colorectal cancer | SREBP-2 | Increasing cellular cholesterol drives intestinal stem cell proliferation and tumorigenesis through SREBP-2 expression (128) |
| SQS | Frequently mutated and dysregulated in liver metastasis (129) | |
| Bladder and endometrial cancer | DHCR24 | Significantly elevated and associated with advanced clinical stage and overall survival (130, 131) |