HDAC1/2 Control Proliferation and Survival in Adult Epidermis and Pre‒Basal Cell Carcinoma through p16 and p53.
HDAC1/2 Control Proliferation and Survival in Adult Epidermis and Pre‒Basal Cell Carcinoma through p16 and p53.
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DOI：
10.1016/j.jid.2021.05.026
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Millar SE
中科院分区：
文献类型：
--
作者：
Zhu X;Leboeuf M;Liu F;Grachtchouk M;Seykora JT;Morrisey EE;Dlugosz AA;Millar SE
HDAC抑制剂显示出对皮肤恶性肿瘤的治疗前景;然而，对特定HDAC在成人表皮稳态和疾病中的作用知之甚少。我们发现，在成年小鼠表皮中，Hdac 1和Hdac 2的纯合表皮共缺失导致基底细胞增殖减少、细胞凋亡、不适当的分化和Hdac 1/2缺失角质形成细胞的最终丧失。hdac 1/2缺陷型表皮显示乙酰化p53升高和衰老基因p16表达增加。p53的缺失部分恢复了基础增殖，而p16缺失促进了Hdac 1/2缺失角质形成细胞的长期存活。在活化的GLI 2驱动的前基底细胞癌中，Hdac 1/2缺失显著降低增殖并增加凋亡，敲除p53或p16部分挽救增殖和基底细胞活力。将HDAC抑制剂罗米地辛局部应用于正常表皮或GLI 2 Δ N驱动的病变会产生与遗传性Hdac 1/2缺失相似的缺陷，这些缺陷通过p16的缺失而得到部分挽救。这些数据揭示了HDAC 1/2在维持成人表皮和基底细胞癌祖细胞增殖和存活中的重要作用，并表明治疗性HDAC 1/2抑制的功效将部分取决于p53和p16的突变状态。
HDAC inhibitors show therapeutic promise for skin malignancies; however, the roles of specific HDACs in adult epidermal homeostasis and disease are poorly understood. We find that homozygous epidermal co-deletion of Hdac1 and Hdac2 in adult mouse epidermis causes reduced basal cell proliferation, apoptosis, inappropriate differentiation, and eventual loss of Hdac1/2-null keratinocytes. Hdac1/2 deficient epidermis displays elevated acetylated p53 and increased expression of the senescence gene p16. Loss of p53 partially restores basal proliferation, whereas p16 deletion promotes long-term survival of Hdac1/2-null keratinocytes. In activated GLI2-driven pre-basal cell carcinoma, Hdac1/2 deletion dramatically reduces proliferation and increases apoptosis, and knockout of either p53 or p16 partially rescues both proliferation and basal cell viability. Topical application of the HDAC inhibitor Romidepsin to normal epidermis or GLI2ΔN-driven lesions produces similar defects to genetic Hdac1/2 deletion, and these are partially rescued by loss of p16. These data reveal essential roles for HDAC1/2 in maintaining proliferation and survival of adult epidermal and basal cell carcinoma progenitors and suggest efficacy of therapeutic HDAC1/2 inhibition will depend in part on the mutational status of p53 and p16.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.5
作者：
Diamond, I;Owolabi, T;Glick, A
通讯作者：
Glick, A
影响因子：
50.3
作者：
Sharpe HJ;Pau G;Dijkgraaf GJ;Basset-Seguin N;Modrusan Z;Januario T;Tsui V;Durham AB;Dlugosz AA;Haverty PM;Bourgon R;Tang JY;Sarin KY;Dirix L;Fisher DC;Rudin CM;Sofen H;Migden MR;Yauch RL;de Sauvage FJ
通讯作者：
de Sauvage FJ
DOI：
10.1111/j.1365-2184.1987.tb01355.x
发表时间：
1987-09-01
期刊：
CELL AND TISSUE KINETICS
影响因子：
--
作者：
POTTEN, CS;SAFFHILL, R;MAIBACH, HI
通讯作者：
MAIBACH, HI
DOI：
10.1073/pnas.93.22.12525
发表时间：
1996-10-29
影响因子：
11.1
作者：
Oh, HS;Smart, RC
通讯作者：
Smart, RC