MiR-34a regulates therapy resistance by targeting HDAC1 and HDAC7 in breast cancer

Therapy resistance increases mortality of cancer patients and remains a major obstacle for cancer treatment. The molecular mechanism underlying the therapy resistance in cancer remains not fully understood, and there is an urgent need to identify the cause of therapy resistance. MiR-34a is an important tumor suppressor whose expression is suppressed in cancer stem cells (CSCs), and re-expression of miR-34a is able to inhibit the tumorigenic activity of CSCs. Because of its tumor suppressor function, elucidating the mechanism by which miR-34a regulates therapy resistance is clearly important but remains a challenge. Our current study addresses this challenge. We identified HDAC1 and HDAC7 as novel targets of miR-34a in breast cancer, and further uncovered that deacetylation of HSP70 K246 by HDAC1 and HDAC7 promotes cancer cell survival and therapy resistance by inhibiting autophagic cell death. Our study is significant as it not only identifies the miR-34a–HDAC1/HDAC7–HSP70 K246 axis as a novel molecular signature predictive of therapy resistance, but also a viable target for potential new anti-cancer therapies to reduce such resistance in breast cancer.     

单羧酸转运蛋白2遗传变异与男性不育的功能和临床相关性

MCT2负责丙酮酸盐和乳酸盐在精子的转运,主要作为能量来源并发挥调节精子活力的作用。我们研究了MCT2基因遗传变异、男性不育、精子MCT2表达水平的关系。我们对MCT2基因的内含子2（＋28201A〉G,rs10506398）和MCT2的3’UTRSNP（MCT2的3’端非翻译区单核苷酸多态性）（＋2626G〉A,rs10506399）的功能和遗传学意义进行研究。两个MCT2基因多态性与男性不育相关（n=471,P〈0．05）。特别是MCT2的3’UTR中SNP（＋2626G〉A）与少弱畸精子症有很强相关性。＋2626GG型的精子数是＋2626AA型的2．4倍（＋2626GG：66×106VS＋2626AA;27×106,P〈0．0001）。由于位于MCT2的3’端,MCT2的3’UTR中SNP对表达有重要作用。＋2626GG型的MCT2蛋白量是＋2626AA型的大约两倍。结果提示MCT2的遗传变异与男性不育有着功能和临床上的相关性。