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The ERα/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells

Bone Research 2022年第1期10卷 95-106页

作者： Zhenqing Liu Hye-Lim Lee Jin Sook Suh Peng Deng Chang-Ryul Lee Olga Bezouglaia Mojan Mirnia Vivian Chen Michael Zhou Zhong-Kai Cui reuben hkim Min Lee Tara Aghaloo Christine Hong Cun-Yu Wang Division of Oral Biology and Medicine School of DentistryUniversity of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA Department of Anatomy&Neurobiology University of CaliforniaIrvine(UCI)IrvineCA 92697USA Department of Orofacial Sciences School of DentistryUniversity of CaliforniaSan Francisco(UCSF)San FranciscoCA 94143USA School of Dentistry University of CaliforniaSan Francisco(UCSF)San FranciscoCA 94143USA Division of Diagnostic and Surgical Sciences School of DentistryUniversity of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA School of Dentistry University of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA Division of Advanced Prosthodontics School of DentistryUniversity of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA Division of Constitutive and Regenerative Sciences School of DentistryUniversity of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA Department of Bioengineering University of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA

Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins(BMPs). The epigenetic regulation of estrogen-mediated osteogenesis,however, is still unclear. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B(KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of ***, upon estrogen stimulation, estrogen receptor-α(ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen’s pro-osteogenic effect was dependent on KDM6B in vivo. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response.

关键词： expression stimulation ERα

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Proinflammatory cytokine TNFα promotes HPV-associated oral carcinogenesis by increasing cancer stemness

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International Journal of Oral Science 2020年第1期12卷 40-49页

作者： Hannah SHong Jonathan Akhavan Sung Hee Lee reuben hkim Mo KKang No-Hee Park Ki-Hyuk Shin The Shapiro Family Laboratory of Viral Oncology and Aging Research UCLA School of DentistryLos AngelesCAUSA UCLA Jonsson Comprehensive Cancer Center Los AngelesCAUSA Department of Medicine David Geffen School of Medicine at UCLALos AngelesCAUSA

High-risk human papillomaviruses(HPVs) are involved in the development of several human cancers, including oropharyngeal squamous cell carcinomas. However, many studies have demonstrated that HPV alone is not sufficient for the oncogenic transformation of normal human epithelial cells, indicating that additional cofactors are required for the oncogenic conversion of HPV-infected cells. Inasmuch as chronic inflammation is also closely associated with carcinogenesis, we investigated the effect of chronic exposure to tumor necrosis factor α(TNFα), the major proinflammatory cytokine, on oncogenesis in two immortalized oral keratinocyte cell lines, namely, HPV16-immortalized and human telomerase reverse transcriptase(h TERT)-immortalized cells. TNFαtreatment led to the acquisition of malignant growth properties in HPV16-immortalized cells, such as(1) calcium resistance,(2)anchorage independence, and(3) increased cell proliferation in vivo. Moreover, TNFα increased the cancer stem cell-like population and stemness phenotype in HPV16-immortalized cells. However, such transforming effects were not observed in h TERTimmortalized cells, suggesting an HPV-specific role in TNFα-promoted oncogenesis. We also generated h TERT-immortalized cells that express HPV16 E6 and E7. Chronic TNFα exposure successfully induced the malignant growth and stemness phenotype in the E6-expressing cells but not in the control and E7-expressing cells. We further demonstrated that HPV16 E6 played a key role in TNFα-induced cancer stemness via suppression of the stemness-inhibiting micro RNAs mi R-203 and mi R-200 c. Overexpression of mi R-203 and mi R-200 c suppressed cancer stemness in TNFα-treated HPV16-immortalized cells. Overall, our study suggests that chronic inflammation promotes cancer stemness in HPV-infected cells, thereby promoting HPV-associated oral carcinogenesis.

关键词： carcinogenesis cytokine cancer

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