HDAC2 in Oncogenesis

描述(申请人提供)：大约85%的人类结直肠癌(CRC)与肿瘤抑制因子腺瘤性息肉病结肠(APC)基因的失活突变有关。功能丧失突变通常是不能用药物治疗的，因为很难恢复失去的功能，但了解APC突变的分子后果以及它们如何与结直肠癌的发展机械地联系起来，可能会为这种疾病提供新的干预方法。小鼠研究表明，其中一个后果是诱导HDAC2(组蛋白脱乙酰酶2)的表达。HDAC2在人类结肠癌中也升高，这表明APC突变介导的HDAC2诱导是APCmin/+小鼠和人类结直肠癌的共同特征。基因敲除内源性HDAC2可减少APCmin/+小鼠的腺瘤形成，表明HDAC2在肠道肿瘤发生中的关键作用，并强烈提示靶向HDAC2可能是治疗结直肠癌的一种有前景的方法。靶向癌症治疗依赖于对癌症靶点的彻底表征和验证，但HDAC2如何促进肠道肿瘤发生仍不清楚。HDAC最广为人知的特征是其脱乙酰酶活性。到目前为止，HDAC2在癌症中的作用完全归因于它的脱乙酰酶活性。然而，我们最近发现HDAC2具有脱乙酰酶非依赖的苏莫化促进活性。根据我们已发表的证据和初步结果，HDAC2促进在人类癌症中起关键作用的底物的总甲基化，我们假设HDAC2总甲基化促进活性有助于肠道肿瘤的发生。在这项应用中，我们将首先对HDAC2促进总酰化活性所需的基序进行详细的表征；然后我们将验证HDAC2促进总甲基化活性在细胞培养和小鼠中的功能作用。这项研究的完成将揭示设计和开发靶向HDAC2总甲基化活性的抑制剂所必需的信息。拟议的实验结果可能会增加对肠道肿瘤发生的新见解，并可能为治疗APC突变的CRC提供替代方法。

DESCRIPTION (provided by applicant): About 85% of human colorectal cancers (CRCs) are associated with inactivation mutations of the tumor suppressor adenomatous polyposis coli (APC) gene. Loss-of-function mutations are generally not drug-able as it is difficult to restore a function that is lost, but understanding the molecular consequences of APC mutation and how they mechanistically link to CRC development could suggest new intervention approaches for this disease. Mice study indicates that one such consequence is the induction of HDAC2 (histone deacetylase 2) expression. HDAC2 is also elevated in human colon cancers, suggesting that APC mutation-mediated HDAC2 induction is a common feature seen in both APCmin/+ mice and human CRC. Genetic knockout of the endogenous HDAC2 diminishes adenoma formation in APCmin/+ mice, indicating the critical role of HDAC2 in intestinal tumorigenesis and strongly suggesting that targeting HDAC2 could be a promising approach for CRC treatment. Targeted cancer therapy relies on a thorough characterization and validation of the cancer target, but how HDAC2 acts to promote intestinal tumorigenesis remains unclear. The best known feature of HDACs is their deacetylase activity. Until now, the role of HDAC2 in cancer is solely attributed to its deacetylase activity. However, we have recently revealed that HDAC2 possesses a deacetylase-independent sumoylation-promoting activity. Based on our published evidence and preliminary results that HDAC2 promotes sumoylation of substrates with pivotal roles in human cancer, we hypothesize that HDAC2 sumoylation-promoting activity contributes to intestinal tumorigenesis. In this application, we will first conduct detailed characterization of the motifs required for HDAC2 sumoylation-promoting activity; we will then validate the functional role of HDAC2 sumoylation- promoting activity in both cell culture and in mice. Completion of the study will reveal information essential for the design and development of inhibitors that target HDAC2 sumoylation activity. The results of the proposed experiments could add new insights into intestinal tumorigenesis, with implication for alternative approach to treating APC-mutated CRC.