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Statin attenuates Wnt/β-catenin signaling by targeting the SATB family of proteins in Colorectal cancer

ABSTRACT: Amongst varied cancers, colorectal cancer (CRC) is the second highest cause for mortality worldwide, suggesting inefficacy of existing medications. Thereby, justifying the need for extensive research to delineate the molecular mechanisms, and evolve new therapies. It has been well established that one of the major pathways responsible for adenoma formation in CRC is the aberrant Wnt/β-catenin signaling. The constant unearthing of it’s molecular players has contributed to a deeper understanding of tumor progression and prognosis, increasing the horizon for targeted therapeutics. One of the methodologies adopted is the repurposing of drugs that target a physiological pathway, known to be dysregulated in tumorigenesis. Hypercholesterolemia has been associated with high-risk CRC patients exclusively, making statins a potential drug for trials in human subjects. Statins are a well-established family of drugs that selectively inhibit de novo cholesterol biosynthesis causing a reduction in systemic cholesterol levels in dyslipidemia. We have contributed to building evidence of statin's anti-tumor activity in both in vitro and in vivo. Our multi-pronged approach provides a holistic view of statin treatment at the lipid, transcript, and protein levels. Interestingly, we observe the Wnt/ β-catenin signaling players getting targeted, one of the most important being SATB (Special AT-rich Binding protein) proteins. Previously, we established the role of SATB1 in tumorigenesis, regulated by β-catenin in Wnt “ON” conditions. On the other hand, SATB2, belonging to the same family, has been reported playing an opposite role. We show that Statins target the physiological balance between the two proteins by downregulating SATB1 and upregulating SATB2. Our phase II trial study in CRC patients further strengthens our hypothesis regarding the differential expression of SATB proteins as a key in determining the tumorigenic outcome. Collectively, these results establish that this molecular switch could provide new therapeutic possibilities in the future, by repurposing statins.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Colon Cancer

SUBMITTER: Siddhesh Kamat

LAB HEAD: Siddhesh S. Kamat

PROVIDER: PXD041210 | Pride | 2025-06-24

REPOSITORIES: Pride

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Project description:Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcomes amongst lung cancer patients suggesting the importance of other pathways. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well defined role in colon and skin cancer but its role in lung cancer remains unclear. We show that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult lung does not promote tumor development by itself. However, activation of Wnt/β- catenin signaling leads to a dramatic increase in tumor formation both in overall tumor number and size compared to KrasG12D alone. We show that activation of Wnt/β- catenin signaling significantly alters the KrasG12D tumor phenotype resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This is associated with a decrease in E- cadherin expression at the cell surface which may increase metastasis in Wnt/β-catenin signaling positive tumors. Together, these data suggest that activation of Wnt/β-catenin signaling in combination with other oncogenic pathways in lung epithelium may lead to a more aggressive phenotype due to the imposition of an embryonic distal progenitor phenotype accompanied by decreased E-cadherin expression. We performed microarray analysis of control murine lung, CC10-cre:KrasG12D, and CC10-cre:Ctnnb1ex3flox:LSL-KrasG12D double mutant micro-dissected murine lung tumors to determine their transcriptional phenotype. Lungs of five-month-old mice were PBS inflated and all the tumors in each lobe were dissected. The total number of tumors obtained from three out of the 5 pulmonar lobes of each animal was called a sample the other two lobes were saved in case there were problems and the array needed to be repeated. Trizol was used to isolate RNA for microarray analysis. Samples & Genotypes: control murine lung n=2 animals, CC10-cre:KrasG12D n=2 animals, and CC10-cre:Ctnnb1ex3flox:LSL-KrasG12D n=2 animals.

			Action	DRS
	116_66_Cont3.group	Other
	116_66_Cont3.wiff	Wiff
	116_66_Cont3.wiff.scan	Wiff
	116_66_Cont3__FDR.xlsx	Xlsx
	116_66_S1.group	Other

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Statin attenuates Wnt/β-catenin signaling by targeting the SATB family of proteins in Colorectal cancer

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