HDAC2 in HDAC inhibitor-based therapy for CRC

描述（由申请人提供）：组蛋白脱乙酰酶抑制剂（HDACis）是一类有前途的新型抗癌药物。两种HDAC被美国FDA许可用于治疗晚期皮肤T细胞淋巴瘤。虽然HDACi作为实体瘤单药治疗的临床试验尚未成功，但HDACi在复发性转移性肺癌患者的联合治疗中显示出希望，这表明当前HDACi的全部治疗潜力可能最好通过与其他抗癌药物联合实现。然而，目前很少有信息来指导临床 HDACi与其它药剂组合的用途。由于结直肠癌（CRC）仍然是一种基本上无法治愈的疾病，因此确定HDACi耐药性的机制至关重要，该机制可以导致增加HDACi在CRC中的治疗潜力的组合策略。该项目的总体目标是揭示HDACi治疗结直肠癌疗效有限的HDAC机制。人类有18种HDAC，这些不同的HDAC在功能上并不冗余。在CRC中，与癌症最相关的HDAC之一是HDAC 2。我们已经发现，在CRC细胞中，HDAC 2敲低增强了SAHA的抗肿瘤作用，而HDAC 2的过表达赋予了对SAHA治疗的抗性。这些发现强烈表明HDAC 2影响HDACi敏感性，并导致CRC细胞对HDACi治疗的不应性。但是HDAC 2的工作机制仍然不清楚。临床证据表明HDACi不应性可能涉及独立于脱乙酰酶抑制的机制。有趣的是，我们发现HDAC 2具有脱乙酰酶独立的sumoylation促进活性，并促进Gsk 3 <$（Wnt信号传导的关键组分）的sumoylation。基于我们的初步结果，我们假设HDAC 2类小泛素化促进活性通过增强Gsk 3类小泛素化上调Wnt/<$-catenin通路而导致CRC细胞中HDACi难治性。在这个提议中，我们将确定Wnt/β-catenin通路在HDAC 2介导的HDACi治疗难治性中的作用。然后，我们将验证HDAC 2类小泛素化促进活性在CRC细胞的HDACi敏感性中的作用。最后，我们将剖析HDAC 2如何通过增强GSK 3类小泛素化来上调Wnt/<$-catenin通路。这项拟议研究的成功完成可能揭示了CRC对HDACi治疗不敏感的可能原因。

DESCRIPTION (provided by applicant): Histone deacetylase inhibitors (HDACis) are a promising new class of anticancer drugs. Two HDACis are licensed by the United States FDA for the treatment of advanced cutaneous T-cell lymphoma. Although clinical trials with HDACis as monotherapy in solid tumors have not been successful, HDACi shows promise in combination therapy for patients with recurrent metastatic lung cancer, suggesting that the full therapeutic potential of current HDACis will probably be best realized through a combination with other anticancer agents. However, currently there is little information to direct the clinical use of HDACi in combination with other agents. As colorectal cancer (CRC) remains an essentially incurable disease, it is critical to identify mechanism of HDACi resistance that can lead to combination strategies that increase HDACi therapeutic potential in CRC. The overall goal of this project is to uncover the HDAC mechanism responsible for the limited efficacy of HDACi treatment in colorectal cancer. There are 18 HDACs in humans and these different HDACs are not redundant in their function. In CRC, one of the most cancer relevant HDACs is HDAC2. We have found that in CRC cells, HDAC2 knockdown enhances the anti-tumor effect of SAHA, whereas overexpression of HDAC2 confers resistance to SAHA treatment. These findings strongly suggest that HDAC2 influences HDACi sensitivity and contributes to refractoriness to HDACi therapy in CRC cells. But the underlying mechanism by which HDAC2 works remains undefined. Clinical evidence suggests that HDACi refractoriness may involve mechanisms independent of deacetylase inhibition. Intriguingly, we have discovered that HDAC2 possesses a deacetylase-independent sumoylation-promoting activity and promotes sumoylation of Gsk3¿ (a key component of Wnt signaling). Based on our preliminary results, we hypothesize that HDAC2 sumoylation-promoting activity contributes to HDACi refractoriness in CRC cells by upregulating the Wnt/¿-catenin pathway through enhancing Gsk3¿ sumoylation. In this proposal, we will determine the role of the Wnt/¿-catenin pathway in HDAC2-mediated refractoriness in HDACi therapy. We will then validate the role of HDAC2 sumoylation-promoting activity in HDACi sensitivity of CRC cells. Finally, we will dissect how HDAC2 upregulates the Wnt/¿-catenin pathway through enhancing Gsk3¿ sumoylation. The successful completion of this proposed study could reveal a possible cause of insensitivity to HDACi treatment in CRC.