HDAC2 in Oncogenesis

描述（由申请人提供）：约85%的人类结直肠癌（CRC）与肿瘤抑制性腺瘤性结肠息肉病（APC）基因的失活突变相关。功能丧失突变通常是不可治疗的，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CRC发展机制联系，可以为这种疾病提出新的干预方法。小鼠研究表明，这样的结果之一是诱导HDAC 2（组蛋白脱乙酰酶2）表达。HDAC 2在人结肠癌中也升高，表明APC突变介导的HDAC 2诱导是APCmin/+小鼠和人CRC中观察到的共同特征。内源性HDAC 2的基因敲除减少了APC min/+小鼠中的腺瘤形成，表明HDAC 2在肠道肿瘤发生中的关键作用，并强烈表明靶向HDAC 2可能是CRC治疗的有希望的方法。靶向癌症治疗依赖于对癌症靶点的彻底表征和验证，但HDAC 2如何促进肠道肿瘤发生仍不清楚。HDAC最为人所知的特征是其脱乙酰酶活性。到目前为止，HDAC 2在癌症中的作用仅归因于其脱乙酰酶活性。然而，我们最近发现，HDAC 2具有脱乙酰酶独立的sumoylation促进活性。基于我们已发表的证据和HDAC 2促进在人类癌症中具有关键作用的底物类小泛素化的初步结果，我们假设HDAC 2类小泛素化促进活性有助于肠道肿瘤发生。在本申请中，我们将首先对HDAC 2类小泛素化促进活性所需的基序进行详细表征;然后我们将验证HDAC 2类小泛素化促进活性在细胞培养物和小鼠中的功能作用。该研究的完成将揭示设计和开发针对HDAC 2类小泛素化活性的抑制剂所必需的信息。拟议实验的结果可以为肠道肿瘤发生提供新的见解，并为治疗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.