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

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.

在各类恶性肿瘤中，结直肠癌（colorectal cancer, CRC）是全球第二大癌症相关致死病因，现有治疗药物疗效欠佳，这凸显了开展深入研究以阐明其分子机制、开发新型治疗方案的必要性。目前已有充分研究证实，结直肠癌腺瘤形成的核心通路之一为异常激活的Wnt/β-连环蛋白（Wnt/β-catenin）信号通路。对该通路分子靶点的持续发掘，加深了学界对肿瘤进展与预后的认知，也拓宽了靶向治疗的研发边界。当前常用的研究策略之一，是针对肿瘤发生过程中失调的生理通路开展药物重定位研究。研究发现，高胆固醇血症仅与高危结直肠癌患者相关，这使得他汀类药物成为人体临床试验的潜在候选药物。他汀类药物是一类已被广泛验证的药物，可选择性抑制胆固醇的从头生物合成，从而降低血脂异常患者的全身胆固醇水平。本团队已通过体外（in vitro）与体内（in vivo）实验，为他汀类药物的抗肿瘤活性积累了充分证据。本研究采用多维度研究策略，从脂质组、转录组与蛋白质组层面全面解析了他汀类药物的作用机制。值得关注的是，我们发现他汀类药物可靶向调控Wnt/β-连环蛋白信号通路的关键分子，其中尤为重要的一类为SATB（特异AT序列结合蛋白，Special AT-rich Binding protein）家族蛋白。此前本团队已证实，SATB1在肿瘤发生中的功能受Wnt通路激活状态下的β-连环蛋白调控；而同家族的SATB2则被报道发挥完全相反的生物学功能。本研究证实，他汀类药物可通过下调SATB1表达、上调SATB2表达，靶向调控这两种蛋白间的生理平衡。针对结直肠癌患者的II期临床试验进一步验证了我们的假说：SATB家族蛋白的差异表达是决定肿瘤发生结局的关键因素。综上，本研究结果表明，这一分子开关可通过药物重定位策略，为结直肠癌治疗提供全新的潜在方向。