Correction: Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development.

[This corrects the article DOI: 10.1371/journal.pone.0017830.].

Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development.

Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer.

Bat3 deficiency accelerates the degradation of Hsp70-2/HspA2 during spermatogenesis.

Meiosis is critical for sexual reproduction. During meiosis, the dynamics and integrity of homologous chromosomes are tightly regulated. The genetic and molecular mechanisms governing these processes in vivo, however, remain largely unknown. In this study, we demonstrate that Bat3/Scythe is essential for survival and maintenance of male germ cells (GCs). Targeted inactivation of Bat3/Scythe in mice results in widespread apoptosis of meiotic male GCs and complete male infertility. Pachytene spermatocytes exhibit abnormal assembly and disassembly of synaptonemal complexes as demonstrated by abnormal SYCP3 staining and sustained gamma-H2AX and Rad51/replication protein A foci. Further investigation revealed that a testis-specific protein, Hsp70-2/HspA2, is absent in Bat3-deficient male GCs at any stage of spermatogenesis; however, Hsp70-2 transcripts are expressed at normal levels. We found that Bat3 deficiency induces polyubiquitylation and subsequent degradation of Hsp70-2. Inhibition of proteasomal degradation restores Hsp70-2 protein levels. Our findings identify Bat3 as a critical regulator of Hsp70-2 in spermatogenesis, thereby providing a possible molecular target in idiopathic male infertility.

Joint regulation of the nmt1 promoter and sporulation by Thi1 and Thi5 in Schizosaccharomyces pombe.

nmt1 in fission yeast is essential for thiamine biosynthesis and is regulated by the thi1 transcription factor. The thiamine-repressible nmt1 promoter is the most widely used promoter construct for gene expression studies in fission yeast. We show that in addition to thi1, thi5 also regulates the nmt1 promoter and its expression is undetectable in a thi1 thi5 double deletion. Thi5 over-expression relieves the repression of nmt1 by thiamine and rescues the thiamine auxotrophy in thi1 deletions. Thi5 may also work to regulate Thi1 activity. Sporulation defects and decreased conjugation were observed in a thi1 disruption; deleting thi5 did not affect conjugation, but resulted in decreased sensitivity to exogenous thiamine. The thi5 deletion is epistatic to thi1 with respect to the failure of the thi1 disruption to produce spores. Thi5 negatively regulates some stages of meiosis. Over-expressing Thi1 from its native promoter results in increased thiamine-insensitive conjugation in all genetic backgrounds, suggesting that Thi1 positively regulates meiosis and that thiamine inhibition of conjugation is a result of Thi1 repression. Thi5 and Thi1 work in the same pathway to positively regulate nmt1 promoter activity. In conjugation, Thi5 and Thi1 operate in different pathways to transcribe antagonists involved in the completion of meiosis.